Drug combinations comprising a DGAT inhibitor and a PPAR-agonist

ABSTRACT

The present invention relates to combinations of a DGAT inhibitor and a peroxisome proliferator-activator receptor (PPAR) agonist or a prodrug thereof.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is the U.S. national stage of Application No.PCT/EP2009/056800, filed Jun. 3, 2009, which application claims priorityfrom PCT/EP2008/057060, filed Jun. 6, 2008; PCT/EP2008/057008, filedJun. 5; 2008; PCT/EP/056983, filed Jun. 5, 2008; PCT/EP2008/057011,filed Jun. 5, 2008 and EP 08170780.4, filed Dec. 5, 2008.

FIELD OF THE INVENTION

This invention concerns novel drug combinations comprising an acylCoA:diacylglycerol acyltransferase (DGAT) inhibitor, in particular aDGAT1 inhibitor, and a peroxisome proliferator-activated receptor (PPAR)agonist, in particular a PPAR-α agonist, pharmaceutical compositionscomprising said novel drug combinations as active ingredients, as wellas the use of said combinations as a medicament and for the manufactureof a medicament.

The present invention also concerns new piperidine/piperazinederivatives having DGAT inhibitory activity, in particular DGAT1inhibitory activity. The invention further relates to methods for theirpreparation and pharmaceutical compositions comprising them. Theinvention also relates to the use of said compounds for the manufactureof a medicament for the prevention or the treatment of a diseasemediated by DGAT, in particular DGAT 1.

BACKGROUND OF THE INVENTION

Triglycerides represent the major form of energy stored in eukaryotes.Disorders or imbalances in triglyceride metabolism are implicated in thepathogenesis of and increased risk for obesity, insulin resistancesyndrome and type II diabetes, nonalcoholic fatty liver disease andcoronary heart disease (see, Lewis, et al, Endocrine Reviews (2002)23:201 and Malloy and Kane, Adv. Intern. Med. (2001) 47:11 1).Additionally, hypertriglyceridemia is often an adverse consequence ofcancer therapy (see, Bast, et al. Cancer Medicament, 5th Ed., (2000) B.C. Decker, Hamilton, Ontario, Calif.).

A key enzyme in the synthesis of triglycerides is acylCoA:diacylglycerol acyltransferase, or DGAT. DGAT is a microsomal enzymethat is widely expressed in mammalian tissues and that catalyzes thejoining of 1,2-diacylglycerol (DAG) and fatty acyl CoA to formtriglycerides (TG) at the endoplasmic reticulum (reviewed in Chen andFarese, Trends Cardiovasc. Med. (2000) 10: 188 and Farese, et al, Curr.Opin. Lipidol. (2000) 11:229). It was originally thought that DGATuniquely controlled the catalysis of the final step of acylation ofdiacylglycerol to triglyceride in the two major pathways fortriglyceride synthesis, the glycerol phosphate and monoacylglycerolpathways. Because triglycerides are considered essential for survival,and their synthesis was thought to occur through a single mechanism,inhibition of triglyceride synthesis through inhibiting the activity ofDGAT has been largely unexplored.

Genes encoding mouse DGAT1 and the related human homologs ARGP1 (humanDGAT1) and ARGP2 (human ACAT2) now have been cloned and characterized(Cases, et al, Pro.c Nat.l Acad. Sci. (1998) 95:13018; Oelkers, et al,J. Biol. Chem. (1998) 273:26765). The gene for mouse DGAT1 has been usedto create DGAT knock-out mice to better elucidate the function of theDGAT gene.

Unexpectedly, mice unable to express a functional DGAT1 enzyme (Dgat1−/−mice) are viable and still able to synthesize triglycerides, indicatingthat multiple catalytic mechanisms contribute to triglyceride synthesis(Smith, et al, Nature Genetics (2000) 25:87). Other enzymes thatcatalyze triglyceride synthesis, for example, DGAT2 and diacylglyceroltransacylase, also have been identified (Cases, et al, J. Biol. Chem.(2001) 276:38870). Gene knockout studies in mice have revealed thatDGAT2 plays a fundamental role in mammalian triglyceride synthesis andis required for survival. DGAT2 deficient mice are lipopenic and diesoon after birth, apparently from profound reductions in substrates forenergy metabolism and from impaired permeability barrier function in theskin. (Farese, et al., J. Biol. Chem. (2004) 279: 11767).

Significantly, Dgat1−/− mice are resistant to diet-induced obesity andremain lean. Even when fed a high fat diet (21% fat) Dgat1−/− micemaintain weights comparable to mice fed a regular diet (4% fat) and havelower total body triglyceride levels. The obesity resistance in Dgat1−/−mice is not due to decreased caloric intake, but the result of increasedenergy expenditure and decreased resistance to insulin and leptin(Smith, et al, Nature Genetics (2000) 25:87; Chen and Farese, TrendsCardiovasc. Med. (2000) 10: 188; and Chen, et al, J. Clin. Invest.(2002) 109:1049). Additionally, Dgat1−/− mice have reduced rates oftriglyceride absorption (Buhman, et al, J. Biol. Chem. (2002)277:25474). In addition to improved triglyceride metabolism, Dgat1−/−mice also have improved glucose metabolism, with lower glucose andinsulin levels following a glucose load, in comparison to wild-type mice(Chen and Farese, Trends Cardiovasc. Med. (2000) 10: 188).

The finding that multiple enzymes contribute to catalyzing the synthesisof triglyceride from diacylglycerol is significant, because it presentsthe opportunity to modulate one catalytic mechanism of this biochemicalreaction to achieve therapeutic results in an individual with minimaladverse side effects. Compounds that inhibit the conversion ofdiacylglycerol to triglyceride, for instance by specifically inhibitingthe activity of DGAT1, will find use in lowering corporealconcentrations and absorption of triglycerides to therapeuticallycounteract the pathogenic effects caused by abnormal metabolism oftriglycerides in obesity, insulin resistance syndrome and overt type IIdiabetes, congestive heart failure and atherosclerosis, and as aconsequence of cancer therapy.

Because of the ever increasing prevalence of obesity, type II diabetes,heart disease and cancer in societies throughout the world, there is apressing need in developing new therapies to effectively treat andprevent these diseases. Therefore there is an interest in developingcompounds that can potently and specifically inhibit the catalyticactivity of DGAT, in particular DGAT1.

We have now unexpectedly found that novel compounds exhibiting DGATinhibitory activity, in particular DGAT1 inhibitory activity, and thesecompounds can therefore be used to prevent or treat a disease associatedwith or mediated by DGAT, such as for example obesity, type II diabetes,heart disease and cancer. The compounds of the invention differ from theprior art compounds in structure, in their pharmacological activity,pharmacological potency, and/or pharmacological profile.

We have also unexpectedly found that DGAT inhibitors, including the DGATinhibitors of the present invention, can be used to elevate the levelsof one or more satiety hormones, in particular glucagon-like-peptide-1(GLP-1) and therefore DGAT inhibitors, in particular DGAT1 inhibitors,can also be used to prevent or treat a disease which can benefit fromelevated levels of a satiety hormone, in particular GLP-1. Glucagon-likepeptide 1 (GLP-1) is an intestinal hormone which generally stimulatesinsulin secretion during hyperglycemia, suppresses glucagon secretion,stimulates (pro) insulin biosynthesis and decelerates gastric emptyingand acid secretion. GLP-1 is secreted from L cells in the small andlarge bowel following the ingestion of fat and proteins. GLP-1 has beensuggested, among other indications, as a possible therapeutic agent forthe management of type II non-insulin-dependent diabetes mellitus aswell as related metabolic disorders, such as obesity.

The present novel compounds make it possible to treat a disease whichcan benefit from elevated levels of GLP-1 with small molecules (comparedto large molecules such as proteins or protein-like compounds, e.g.GLP-1 analogues).

The peroxisome proliferator-activated receptors (PPAR) belong to thesteroid hormone nuclear receptor superfamily of ligand-activatedtranscription factors that mediate the specific effects of smalllipophilic compounds, such as steroids, retinoids and fatty acids, onDNA transcription. They play an important role in the regulation oflipid metabolism, in the regulation of energy homeostasis, inflammation,artherosclerosis and glucose control. Three subtypes are identified sofar, namely PPAR-α, PPAR-β/δ and PPAR-γ. The three isoforms exhibitdifferent tissue distribution as well as different ligand specificities.

PPAR-α plays a crucial role in the intracellular lipid metabolism. ThePPAR-α subtype is mainly expressed in tissues with elevatedmitochondrial and peroxisomal fatty acid β-oxidation rates, thatefficiently harvest energy from lipids, including liver, skeletalmuscle, heart muscle, proximal tubular epithelial cells of the kidney,and brown fat (brown adipose tissue). PPAR-α is also present in cells ofthe arterial wall, in monocytes/macrophages, smooth muscle cells,endothelial cells, in hepatocytes, and in cardiac myocytes.

Saturated and unsaturated fatty acids are found to be the primarynatural PPAR-α ligands. In general, PPAR-α can be activated by aheterogeneous group of compounds, which include natural and syntheticagonists, such as eicosanoids, leukotriene β₄, carbaprostacyclin,nonsteroidal anti-inflammatory drugs, pirinixic acid (WY-14643; PPAR-α/γagonist), phthalate ester plasticizers, pterostilbene, fibrates oractive metabolites thereof, α-substituted phenyl-propanoic acidderivatives and isoxazolyl-serine-based compounds. Finally, PPAR-α isinduced by glucocorticoids in response to stress and follows a diurnalrhythm.

Fibrates or active metabolites thereof such as fibric acid derivatives,are PPAR-α agonists, and have been used to treat dyslipidemia forseveral decades because of their triglyceride lowering and high-densitylipoprotein (HDL) cholesterol elevating effects. Fibric acid derivativeslower the levels of triglyceride-rich lipoproteins, such as verylow-density lipoproteins (VLDL), raise HDL levels, and have variableeffect on low-density lipoproteins (LDL) levels. The effects on VLDLlevels appear to result primarily from an increase in lipoprotein lipaseactivity, especially in muscle. This leads to enhanced hydrolysis ofVLDL triglyceride content and an enhanced VLDL catabolism. Fibric acidagents also may alter the composition of the VLDL, for example, bydecreasing hepatic production of apoC-III, an inhibitor of lipoproteinlipase activity. These compounds are also reported to decrease hepaticVLDL triglyceride synthesis, possibly by inhibiting fatty acid synthesisand by promoting fatty acid oxidation. In addition, they have beendocumented to be beneficial in the prevention of ischemic heart diseasein individuals with dyslipidemia and they can also modestly decreaseelevated fibrinogen and PAI-1 levels. Well-known examples of fibratesare fenofibrate (fenofibric acid as active metabolite), ABT-335 (whichis the choline salt of fenofibric acid), bezafibrate, clofibrate,ciprofibrate, etofibrate, pirifibrate, beclofibrate and gemfibrozil(PPAR-α modulator).

Because of the ever increasing prevalence of obesity, type II diabetes,heart disease and cancer in societies throughout the world, there is apressing need in developing new therapies to effectively treat andprevent these diseases.

We have now unexpectedly found that the combination of a compoundshowing DGAT inhibitory activity, in particular DGAT1 inhibitoryactivity, with a PPAR agonist, in particular a PPAR-α agonist, mayexhibit an increased and/or accelerated effect on weight loss, comparedto the effect of the DGAT inhibitor or the PPAR agonist each separately,and additional can decrease food intake. The combinations of the presentinvention may show synergy compared to administration of the composingingredients alone.

BACKGROUND PRIOR ART

WO 2006/034441 discloses heterocyclic derivatives and their use asstearoyl CoA desaturase inhibitors (SCD-1 inhibitors).

WO 2006/086445 relates to a combination therapy of a SCD-1 inhibitor andanother drug to treat adverse weight gain.

WO 2006/004200 and JP2007131584 relate to urea and amino derivativeshaving DGAT inhibitory activity.

WO 2004/047755 relates to fused bicyclic nitrogen-containingheterocycles having DGAT inhibitory activity.

WO2005/072740 relates to an anorectic action of a compound having DGATinhibitory activity.

WO 2007/071966 discloses a conjoint treatment ofpyrimido-[4,5-B]-oxazines showing DGAT inhibitory activity together withanti-dyslipidaemia agents such as PPAR-α agonists.

WO2008/148851, WO2008/148840, WO2008/148849 and WO2008/148868 concernpiperidine/piperazine derivatives having DGAT inhibitory activity.

DESCRIPTION OF THE DRAWINGS

FIG. A1 shows the food intake of mice treated with a DGAT inhibitor(compound 223 of Class D—called D in FIG. A1), fenofibrate (F) or both,compared to the control group. ‘BL’ means baseline food intake.

FIG. A2 shows the change in body weight (g) of DIO C57BL/6 mice treatedwith a DGAT inhibitor (compound 223 of Class D—25 mpk/d), fenofibrate(31 mpk/d) or both.

FIG. B1 shows the food intake of DIO C57BL/6 mice fed with a high-fatdiet containing fenofibrate (F) and compound 223 of Class D (D).

FIG. B2 shows the body weight change of DIO C57BL/6 mice fed with ahigh-fat diet containing fenofibrate (F) and compound 223 of Class D(D).

FIG. B3 shows food intake on day 1 of DIO C57BL/6 mice fed with ahigh-fat diet containing compound 223 of Class D and fenofibrate (D+F).

FIG. C1 shows the high fat diet intake (g) of DIO C57BL/6 mice treatedwith a DGAT inhibitor (compound 358 of Class D), fenofibrate (F) orboth, compared to the control group.

FIG. C2 shows the change in body weight (g) of DIO C57BL/6 mice fed witha high-fat diet containing DGAT inhibitor (compound 358 of Class D),fenofibrate or both.

FIG. D1 shows food intake of lean C57BL/6 mice fed a low-fat dietcontaining compound 223 of Class D (D) and fenofibrate (F).

FIG. D2 shows food intake of lean C57BL/6 mice fed a high-fat dietcontaining compound 223 of Class D (D) and fenofibrate (F).

FIG. D3 shows day-1 food intake of mice fed a low and high-fat dietcontaining 0.01/0.0125% w/w compound 223 of Class D/fenofibrate (D/F).DIO C57BL/6 mice were acclimated to cages designed for measuring foodintake. After adaptation to either a low-fat (10 kcal % fat) or high-fat(45 kcal % fat) diet, mice were switched to a diet with the same fatcontent (10 kcal % and 45 kcal % fat respectively), but supplementedwith 0.01/0.0125% w/w D/F.

DESCRIPTION OF THE INVENTION

The present invention relates to combinations of a DGAT inhibitor and aperoxisome proliferator-activator receptor (PPAR) agonist or a prodrugthereof.

In an embodiment, the present invention relates to combinations of aDGAT inhibitor and a PPAR-α agonist or a prodrug thereof.

In an embodiment, the present invention relates to combinations of aDGAT1 inhibitor and a PPAR agonist or a prodrug thereof.

In an embodiment, the present invention relates to combinations of aDGAT1 inhibitor and a PPAR-α agonist or a prodrug thereof.

In an embodiment, the present invention relates to combinations of aDGAT inhibitor, in particular a DGAT1 inhibitor, and a PPAR-α agonist ora prodrug thereof selected from the group of fibrates.

In an embodiment, the present invention relates to combinations of aDGAT inhibitor, in particular a DGAT1 inhibitor, and fenofibrate.

In an embodiment, the present invention relates to combinations of aPPAR agonist or a prodrug thereof and a DGAT inhibitor wherein the DGATinhibitor is selected from

-   a) a compound having the formula

including any stereochemically isomeric form thereof, wherein

-   A represents CH or N;-   X represents O or NR^(x);-   the dotted line represents an optional bond in case A represents a    carbon atom;-   Y represents a direct bond; —NR^(x)—C(═O)—; —C(═O)—NR^(x)—;    —NR^(x)—C(═O)—Z—; —NR^(x)—C(═O)—Z—NR^(y)—;    —NR^(x)—C(═O)—Z—NR^(y)—C(═O)—; —NR^(x)—C(═O)—Z—NR^(y)—C(═O)—O—;    —NR^(x)—C(═O)—Z—O—; —NR^(x)—C(═O)—Z—O—C(═O)—;    —NR^(x)—C(═O)—Z—C(═O)—; —NR^(x)—C(═O)—Z—C(═O)—O—;    —NR^(x)—C(═O)—O—Z—C(═O)—; —NR^(x)—C(═O)—O—Z—C(═O)—O—;    —NR^(x)—C(═O)—O—Z—O—C(═O)—; —NR^(x)—C(═O)—Z—C(═O)—NR^(y)—;    —NR^(x)—C(═O)—Z—NR^(y)—C(═O)—NR^(y)—; —C(═O)—Z—; —C(═O)—Z—O—;    —C(═O)—NR^(x)—Z—; —C(═O)—NR^(x)—Z—O—; —C(═O)—NR^(x)—Z—C(═O)—O—;    —C(═O)—NR^(x)—Z—O—C(═O)—; —C(═O)—NR^(x)—O—Z—;    —C(═O)—NR^(x)—Z—NR^(y)—; —C(═O)—NR^(x)—Z—NR^(y)—C(═O)—;    —C(═O)—NR^(x)—Z—NR^(y)—C(═O)—O—;-   Z represents a bivalent radical selected from C₁₋₆alkanediyl,    C₂₋₆alkenediyl or C₂₋₆alkynediyl; wherein each of said    C₁₋₆alkanediyl, C₂₋₆alkenediyl or C₂₋₆alkynediyl may optionally be    substituted with C₁₋₄alkyloxy, C₁₋₄alkylthio, hydroxyl, cyano or    aryl; and wherein two hydrogen atoms attached to the same carbon    atom in the definition of Z may optionally be replaced by    C₁₋₆alkanediyl;-   R^(x) represents hydrogen or C₁₋₄alkyl;-   R^(y) represents hydrogen; C₁₋₄alkyl optionally substituted with    C₃₋₆cycloalkyl or aryl or Het; C₂₋₄alkenyl; or —S(═O)_(p)-aryl;-   R¹ represents C₁₋₁₂alkyl optionally substituted with cyano,    C₁₋₄alkyloxy, C₁₋₄alkyl-oxyC₁₋₄alkyloxy, C₃₋₆cycloalkyl or aryl;    C₂₋₆alkenyl; C₂₋₆alkynyl; C₃₋₆cycloalkyl; aryl¹; aryl¹C₁₋₆alkyl;    Het¹; or Het¹C₁₋₆alkyl; provided that when Y represents    —NR^(x)—C(═O)—Z—; —NR^(x)—C(═O)—Z—NR^(y);    —NR^(x)—C(═O)—Z—C(═O)—NR^(y)—; —C(═O)—Z—;    —NR^(x)—C(═O)—Z—NR^(y)—C(═O)—NR^(y)—; —C(═O)—NR^(x)—Z—;    —C(═O)—NR^(x)—O—Z—; or —C(═O)—NR^(x)—Z—NR^(y)—; then R¹ may also    represent hydrogen;-   R² and R³ each independently represent hydrogen; hydroxyl; carboxyl;    halo; C₁₋₆alkyl; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally    substituted with C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy;    C₁₋₆alkyloxycarbonyl; cyano; aminocarbonyl; mono- or    di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono-    or di(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl;-   R⁴ represents hydrogen; hydroxyl; carboxyl; halo; C₁₋₆alkyl;    polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted with    C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhalo-C₁₋₆alkyloxy;    C₁₋₆alkyloxycarbonyl wherein C₁₋₆alkyl may optionally be substituted    with aryl; cyano; C₁₋₆alkylcarbonyl; nitro; amino; mono- or    di(C₁₋₄alkyl)amino; C₁₋₄alkylcarbonylamino; —S(═O)_(p)—C₁₋₄alkyl;    R⁶R⁵N—C(═O)—; R⁶R⁵N—C₁₋₆alkyl; C₃₋₆cycloalkyl; aryl; aryloxy;    arylC₁₋₄alkyl; aryl-C(═O)—C₁₋₄alkyl; aryl-C(═O)—; Het; HetC₁₋₄alkyl;    Het-C(═O)—C₁₋₄alkyl; Het-C(═O)—; Het-O—;-   R⁵ represents hydrogen; C₁₋₄alkyl optionally substituted with    hydroxyl or C₁₋₄alkyloxy; R⁸R⁷N—C₁₋₄alkyl; C₁₋₄alkyloxy; Het; aryl;    R⁸R⁷N—C(═O)—C₁₋₄alkyl;-   R⁶ represents hydrogen or C₁₋₄alkyl;-   R⁷ represents hydrogen; C₁₋₄alkyl; C₁₋₄alkylcarbonyl;-   R⁸ represents hydrogen or C₁₋₄alkyl; or-   R⁷ and R⁸ may be taken together with the nitrogen to which they are    attached to form a saturated monocyclic 5, 6 or 7-membered    heterocycle which may further contain one or more heteroatoms each    independently selected from O, S, S(═O)_(p) or N; and which    heterocycle may optionally be substituted with C₁₋₄alkyl;-   R⁹ represents hydrogen, halo, C₁₋₄alkyl, C₁₋₄alkyl substituted with    hydroxyl;-   aryl represents phenyl or phenyl substituted with at least one    substituent, in particular one, two, three, four or five    substituents, each substituent independently being selected from    hydroxyl; carboxyl; halo; C₁₋₆alkyl optionally substituted with    C₁₋₄alkyloxy, amino or mono- or di(C₁₋₄alkyl)amino;    polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted with    C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy;    C₁₋₆alkyloxycarbonyl; cyano; aminocarbonyl; mono- or    di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono-    or di(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl;-   aryl¹ represents phenyl, naphthalenyl or fluorenyl; each of said    phenyl, naphthalenyl or fluorenyl optionally substituted with at    least one substituent, in particular one, two, three, four or five    substituents, each substituent independently being selected from    hydroxyl; oxo; carboxyl; halo; C₁₋₆alkyl optionally substituted with    carboxyl, C₁₋₄alkyloxycarbonyl or aryl-C(═O)—; hydroxyC₁₋₆alkyl    optionally substituted with aryl or aryl-C(═O)—; polyhaloC₁₋₆alkyl;    C₁₋₆alkyloxy optionally substituted with C₁₋₄alkyloxy;    C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy; C₁₋₆alkyloxy-carbonyl wherein    C₁₋₆alkyl may optionally be substituted with aryl; cyano;    aminocarbonyl; mono- or di(C₁₋₄alkyl)aminocarbonyl;    C₁₋₆alkylcarbonyl; amino; mono- or di(C₁₋₆alkyl)amino;    R⁶R⁵N—C₁₋₆alkyl; C₃₋₆cycloalkyl-NR^(x)—; aryl-NR^(x)—; Het-NR^(x)—;    C₃₋₆cycloalkylC₁₋₄alkyl-NR^(x)—; arylC₁₋₄alkyl-NR^(x)—;    HetC₁₋₄alkyl-NR^(x)—; —S(═O)_(p)—C₁₋₄alkyl; C₃₋₆cycloalkyl;    C₃₋₆cycloalkylC₁₋₄alkyl; C₃₋₆cycloalkyl-C(═O)—; aryl; aryloxy;    arylC₁₋₄alkyl; aryl-C(═O)—; aryl-C(═O)—C₁₋₄alkyl; Het; HetC₁₋₄alkyl;    Het-C(═O)—; Het-C(═O)—C₁₋₄alkyl; Het-O—;-   Het represents a monocyclic non-aromatic or aromatic heterocycle    containing at least one heteroatom each independently selected from    O, S, S(═O)_(p) or N; or a bicyclic or tricyclic non-aromatic or    aromatic heterocycle containing at least one heteroatom each    independently selected from O, S, S(═O)_(p) or N; said monocyclic    heterocycle or said bi- or tricyclic heterocycle optionally being    substituted with at least one substituent, in particular one, two,    three, four or five substituents, each substituent independently    being selected from hydroxyl; oxo; carboxyl; halo; C₁₋₆alkyl    optionally substituted with C₁₋₄alkyloxy, amino or mono- or    di(C₁₋₄alkyl)amino; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally    substituted with C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy;    C₁₋₆ alkyl-oxycarbonyl; cyano; aminocarbonyl; mono- or    di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono-    or di(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl;-   Het¹ represents a monocyclic non-aromatic or aromatic heterocycle    containing at least one heteroatom each independently selected from    O, S, S(═O)_(p) or N; or a bicyclic or tricyclic non-aromatic or    aromatic heterocycle containing at least one heteroatom each    independently selected from O, S, S(═O)_(p) or N; said monocyclic    heterocycle or said bi- or tricyclic heterocycle optionally being    substituted with at least one substituent, in particular one, two,    three, four or five substituents, each substituent independently    being selected from hydroxyl; oxo; carboxyl; halo; C₁₋₆alkyl    optionally substituted with carboxyl, C₁₋₄alkyloxycarbonyl or    aryl-C(═O)—; hydroxyC₁₋₆alkyl optionally substituted with aryl or    aryl-C(═O)—; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted    with C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy;    C₁₋₆alkyloxy-carbonyl wherein C₁₋₆alkyl may optionally be    substituted with aryl; cyano; aminocarbonyl; mono- or    di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; amino; mono- or    di(C₁₋₆alkyl)amino; R⁶R⁵N—C₁₋₆alkyl; C₃₋₆cycloalkyl-NR^(x)—;    aryl-NR^(x)—; Het-NR^(x)—; C₃₋₆cycloalkylC₁₋₄alkyl-NR^(x)—;    arylC₁₋₄alkyl-NR^(x)—; HetC₁₋₄alkyl-NR^(x)—; —S(═O)_(p)—C₁₋₄alkyl;    C₃₋₆cycloalkyl; C₃₋₆cycloalkylC₁₋₄alkyl; C₃₋₆cycloalkyl-C(═O)—;    aryl; aryloxy; arylC₁₋₄alkyl; aryl-C(═O)—; aryl-C(═O)—C₁₋₄alkyl;    Het; HetC₁₋₄alkyl; Het-C(═O)—; Het-C(═O)—C₁₋₄alkyl; Het-O—;-   p represents 1 or 2;    a N-oxide thereof, a pharmaceutically acceptable salt thereof or a    solvate thereof;-   b) a compound having the formula

including any stereochemically isomeric form thereof, wherein

-   A represents CH or N;    the dotted line represents an optional bond in case A represents a    carbon atom;-   X represents —NR^(x)—C(═O)—; —Z—C(═O)—; —Z—NR^(x)—C(═O)—;    —S(═O)_(p)—; —C(═S)—; —NR^(x)—C(═S)—; —Z—C(═S)—; —Z—NR^(x)—C(═S)—;    —O—C(═O)—; —C(═O)—C(═O)—;-   Z represents a bivalent radical selected from C₁₋₆alkanediyl,    C₂₋₆alkenediyl or C₂₋₆alkynediyl; wherein each of said    C₁₋₆alkanediyl, C₂₋₆alkenediyl or C₂₋₆alkynediyl may optionally be    substituted with hydroxyl or amino; and wherein two hydrogen atoms    attached to the same carbon atom in C₁₋₆alkanediyl may optionally be    replaced by C₁₋₆alkanediyl;-   R^(x) represents hydrogen or C₁₋₄alkyl;-   R¹ represents a 5-membered monocyclic heterocycle containing at    least 2 heteroatoms; a 6-membered aromatic monocyclic heterocycle;    or a 5-membered heterocycle containing at least 2 heteroatoms fused    with phenyl, cyclohexyl or a 5- or 6-membered heterocycle; wherein    each of said heterocycles may optionally be substituted with at    least one substituent, in particular one, two, three, four or five    substituents, each substituent independently being selected from    hydroxyl; oxo; carboxyl; halo; C₁₋₆alkyl optionally substituted with    carboxyl, C₁₋₄alkyloxycarbonyl or aryl-C(═O)—; hydroxyC₁₋₆alkyl    optionally substituted with aryl or aryl-C(═O)—; polyhaloC₁₋₆alkyl;    C₁₋₆alkyloxy optionally substituted with C₁₋₄alkyloxy;    C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy; C₁₋₆alkyloxy-carbonyl wherein    C₁₋₆alkyl may optionally be substituted with aryl; cyano;    aminocarbonyl; mono- or di(C₁₋₄alkyl)-aminocarbonyl;    C₁₋₆alkylcarbonyl; amino; mono- or di(C₁₋₆alkyl)amino;    R⁵R⁴N—C₁₋₆alkyl; C₃₋₆cycloalkyl-NR^(x)—; aryl-NR^(x)—; Het-NR^(x)—;    C₃₋₆cycloalkyl-C₁₋₄alkyl-NR^(x)—; arylC₁₋₄alkyl-NR^(x)—;    HetC₁₋₄alkyl-NR^(x)—; —S(═O)_(p)—C₁₋₄alkyl; C₃₋₆cycloalkyl;    C₃₋₆cycloalkylC₁₋₄alkyl; C₃₋₆cycloalkyl-C(═O)—; aryl; aryloxy;    arylC₁₋₄alkyl; aryl-C(═O)—; aryl-C(═O)—C₁₋₄alkyl; Het; HetC₁₋₄alkyl;    Het-C(═O)—; Het-C(═O)—C₁₋₄alkyl; Het-O—;-   R² represents R³;-   R³ represents C₃₋₆cycloalkyl, phenyl, naphtalenyl,    2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl,    2,3-dihydrobenzofuranyl or a 6-membered aromatic heterocycle    containing 1 or 2 N atoms, wherein said C₃₋₆cycloalkyl, phenyl,    naphtalenyl, 2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl,    2,3-dihydrobenzofuranyl or 6-membered aromatic heterocycle may    optionally be substituted with at least one substituent, in    particular one, two, three, four or five substituents, each    substituent independently selected from hydroxyl; carboxyl; halo;    C₁₋₆alkyl optionally substituted with hydroxy; polyhaloC₁₋₆alkyl;    C₁₋₆alkyloxy optionally substituted with C₁₋₄alkyloxy;    C₁₋₆alkylthio; polyhalo-C₁₋₆alkyloxy; C₁₋₆alkyloxycarbonyl wherein    C₁₋₆alkyl may optionally be substituted with aryl; cyano;    C₁₋₆alkylcarbonyl; nitro; amino; mono- or di(C₁₋₄alkyl)amino;    C₁₋₄alkylcarbonylamino; —S(═O)_(p)—C₁₋₄alkyl; R⁵R⁴N—C(═O)—;    R⁵R⁴N—C₁₋₆alkyl; C₃₋₆cycloalkyl; C₃₋₆cycloalkylC₁₋₄alkyl;    C₃₋₆cycloalkyl-C(═O)—; aryl; aryloxy; arylC₁₋₄alkyl;    aryl-C(═O)—C₁₋₄alkyl; aryl-C(═O)—; Het; HetC₁₋₄alkyl;    Het-C(═O)—C₁₋₄alkyl; Het-C(═O)—; Het-O—;-   R⁴ represents hydrogen; C₁₋₄alkyl optionally substituted with    hydroxyl or C₁₋₄alkyloxy; R⁷R⁶N—C₁₋₄alkyl; C₁₋₄alkyloxy; Het; aryl;    R⁷R⁶N—C(═O)—C₁₋₄alkyl;-   R⁵ represents hydrogen or C₁₋₄alkyl;-   R⁶ represents hydrogen; C₁₋₄alkyl; C₁₋₄alkylcarbonyl;-   R⁷ represents hydrogen or C₁₋₄alkyl; or-   R⁶ and R⁷ may be taken together with the nitrogen to which they are    attached to form a saturated monocyclic 5, 6 or 7-membered    heterocycle which may further contain one or more heteroatoms    selected from O, S, S(═O)_(p) or N; and which heterocycle may    optionally be substituted with C₁₋₄alkyl;-   R⁸ represents hydrogen, halo, C₁₋₄alkyl, C₁₋₄alkyl substituted with    hydroxyl;-   aryl represents phenyl or phenyl substituted with at least one    substituent, in particular one, two, three, four or five    substituents, each substituent independently being selected from    hydroxyl; carboxyl; halo; C₁₋₆alkyl optionally substituted with    C₁₋₄alkyloxy, amino or mono- or di(C₁₋₄alkyl)amino;    polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted with    C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy;    C₁₋₆alkyloxycarbonyl; cyano; aminocarbonyl; mono- or    di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono-    or di(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl;-   Het represents a monocyclic non-aromatic or aromatic heterocycle    containing at least one heteroatom selected from O, S, S(═O)_(p) or    N; or a bicyclic or tricyclic non-aromatic or aromatic heterocycle    containing at least one heteroatom selected from O, S, S(═O)_(p) or    N; said monocyclic heterocycle or said bi- or tricyclic heterocycle    optionally being substituted with at least one substituent, in    particular one, two, three, four or five substituents, each    substituent independently being selected from hydroxyl; oxo;    carboxyl; halo; C₁₋₆alkyl optionally substituted with C₁₋₄alkyloxy,    amino or mono- or di(C₁₋₄alkyl)amino; polyhaloC₁₋₆alkyl;    C₁₋₆alkyloxy optionally substituted with C₁₋₄alkyloxy;    C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy; C₁₋₆alkyl-oxycarbonyl; cyano;    aminocarbonyl; mono- or di(C₁₋₄alkyl)aminocarbonyl;    C₁₋₆alkylcarbonyl; nitro; amino; mono- or di(C₁₋₄alkyl)amino;    —S(═O)_(p)—C₁₋₄alkyl-   p represents 1 or 2;    a N-oxide thereof, a pharmaceutically acceptable salt thereof or a    solvate thereof;-   c) a compound having the formula

including any stereochemically isomeric form thereof, wherein

-   A represents CH or N;    the dotted line represents an optional bond in case A represents a    carbon atom;-   X represents —O—C(═O)—; —C(═O)—C(═O)—; —NR^(x)—C(═O)—; —Z—C(═O)—;    —Z—NR^(x)—C(═O)—; —C(═O)—Z—; —NR^(x)—C(═O)—Z—; —C(═S)—; —S(═O)_(p)—;    —NR^(x)—C(═S)—; —Z—C(═S)—; —Z—NR^(x)—C(═S)—; —C(═S)—Z—;    —NR^(x)—C(═S)—Z—;-   Z represents a bivalent radical selected from C₁₋₆alkanediyl,    C₂₋₆alkenediyl or C₂₋₆alkynediyl; wherein each of said    C₁₋₆alkanediyl, C₂₋₆alkenediyl or C₂₋₆alkynediyl may optionally be    substituted with hydroxyl or amino; and wherein two hydrogen atoms    attached to the same carbon atom in C₁₋₆alkanediyl may optionally be    replaced by C₁₋₆alkanediyl;-   R^(x) represents hydrogen or C₁₋₄alkyl;-   Y represents —C(═O)—NR^(x)— or —NR^(x)—C(═O)—;-   R¹ represents adamantanyl, C₃₋₆cycloalkyl; aryl¹ or Het¹;-   R² represents hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₃₋₆cycloalkyl,    phenyl, naphtalenyl, 2,3-dihydro-1,4-benzodioxinyl,    1,3-benzodioxolyl, 2,3-dihydrobenzofuranyl or a 6-membered aromatic    heterocycle containing 1 or 2 N atoms, wherein said C₃₋₆cycloalkyl,    phenyl, naphtalenyl, 2,3-dihydro-1,4-benzodioxinyl,    1,3-benzodioxolyl or 6-membered aromatic heterocycle containing 1 or    2 N atoms may optionally be substituted with at least one    substituent, in particular one, two, three, four or five    substituents, each substituent independently selected from hydroxyl;    carboxyl; halo; C₁₋₆alkyl optionally substituted with hydroxy;    polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted with    C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhalo-C₁₋₆alkyloxy;    C₁₋₆alkyloxycarbonyl wherein C₁₋₆alkyl may optionally be substituted    with aryl; cyano; C₁₋₆alkylcarbonyl; nitro; amino; mono- or    di(C₁₋₄alkyl)amino; C₁₋₄alkylcarbonylamino; —S(═O)_(p)—C₁₋₄alkyl;    R⁴R³N—C(═O)—; R⁴R³N—C₁₋₆alkyl; C₃₋₆cycloalkyl;    C₃₋₆cycloalkylC₁₋₄alkyl; C₃₋₆cycloalkyl-C(═O)—; aryl; aryloxy;    arylC₁₋₄alkyl; aryl-C(═O)—C₁₋₄alkyl; aryl-C(═O)—; Het; HetC₁₋₄alkyl;    Het-C(═O)—C₁₋₄alkyl; Het-C(═O)—; Het-O—;-   R³ represents hydrogen; C₁₋₄alkyl optionally substituted with    hydroxyl or C₁₋₄alkyloxy; R⁶R⁵N—C₁₋₄alkyl; C₁₋₄alkyloxy; Het;    Het-C₁₋₄alkyl; aryl; R⁶R⁵N—C(═O)—C₁₋₄alkyl;-   R⁴ represents hydrogen or C₁₋₄alkyl;-   R⁵ represents hydrogen; C₁₋₄alkyl; C₁₋₄alkylcarbonyl;-   R⁶ represents hydrogen or C₁₋₄alkyl; or-   R⁵ and R⁶ may be taken together with the nitrogen to which they are    attached to form a saturated monocyclic 5, 6 or 7-membered    heterocycle which may further contain one or more heteroatoms each    independently selected from O, S, S(═O)_(p) or N; and which    heterocycle may optionally be substituted with C₁₋₄alkyl;-   R⁷ represents hydrogen, halo, C₁₋₄alkyl, C₁₋₄alkyl substituted with    hydroxyl;-   aryl represents phenyl or phenyl substituted with at least one    substituent, in particular one, two, three, four or five    substituents, each substituent independently being selected from    hydroxyl; carboxyl; halo; C₁₋₆alkyl optionally substituted with    C₁₋₄alkyloxy, amino or mono- or di(C₁₋₄alkyl)amino;    polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted with    C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy;    C₁₋₆alkyloxycarbonyl; cyano; aminocarbonyl; mono- or    di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono-    or di(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl;-   aryl¹ represents phenyl, naphthalenyl or fluorenyl; each of said    phenyl, naphthalenyl or fluorenyl optionally substituted with at    least one substituent, in particular one, two, three, four or five    substituents, each substituent independently being selected from    hydroxyl; oxo; carboxyl; halo; C₁₋₆alkyl optionally substituted with    carboxyl, C₁₋₄alkyloxycarbonyl or aryl-C(═O)—; hydroxyC₁₋₆alkyl    optionally substituted with aryl or aryl-C(═O)—; polyhaloC₁₋₆alkyl;    C₁₋₆alkyloxy optionally substituted with C₁₋₄alkyloxy;    C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy; C₁₋₆alkyloxy-carbonyl wherein    C₁₋₆alkyl may optionally be substituted with aryl; cyano;    aminocarbonyl; mono- or di(C₁₋₄alkyl)aminocarbonyl;    C₁₋₆alkylcarbonyl; nitro; amino; mono- or di(C₁₋₆alkyl)amino;    R⁴R³N—C₁₋₆alkyl; C₃₋₆cycloalkyl-NR^(x)—; aryl-NR^(x)—; Het-NR^(x)—;    C₃₋₆cycloalkylC₁₋₄alkyl-NR^(x)—; arylC₁₋₄alkyl-NR^(x)—;    HetC₁₋₄alkyl-NR^(x)—; —S(═O)_(p)—C₁₋₄alkyl; C₃₋₆cycloalkyl;    C₃₋₆cycloalkylC₁₋₄alkyl; C₃₋₆cycloalkyl-C(═O)—; aryl; aryloxy;    arylC₁₋₄alkyl; aryl-C(═O)—C₁₋₄alkyl; aryl-C(═O)—; Het; HetC₁₋₄alkyl;    Het-C(═O)—C₁₋₄alkyl; Het-C(═O)—; Het-O—;-   Het represents a monocyclic non-aromatic or aromatic heterocycle    containing at least one heteroatom each independently selected from    O, S, S(═O)_(p) or N; or a bicyclic or tricyclic non-aromatic or    aromatic heterocycle containing at least one heteroatom each    independently selected from O, S, S(═O)_(p) or N; said monocyclic    heterocycle or said bi- or tricyclic heterocycle optionally being    substituted with at least one substituent, in particular one, two,    three, four or five substituents, each substituent independently    being selected from hydroxyl; oxo; carboxyl; halo; C₁₋₆alkyl    optionally substituted with C₁₋₄alkyloxy, amino or mono- or    di(C₁₋₄alkyl)amino; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally    substituted with C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy;    C₁₋₆alkyloxycarbonyl; cyano; aminocarbonyl; mono- or    di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono-    or di(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl;-   Het¹ represents a monocyclic non-aromatic or aromatic heterocycle    containing at least one heteroatom each independently selected from    O, S, S(═O)_(p) or N; or a bicyclic or tricyclic non-aromatic or    aromatic heterocycle containing at least one heteroatom each    independently selected from O, S, S(═O)_(p) or N; said monocyclic    heterocycle or said bi- or tricyclic heterocycle optionally being    substituted with at least one substituent, in particular one, two,    three, four or five substituents, each substituent independently    being selected from hydroxyl; oxo; carboxyl; halo; C₁₋₆alkyl    optionally substituted with aryl-C(═O)—; hydroxyC₁₋₆alkyl optionally    substituted with aryl or aryl-C(═O)—; polyhaloC₁₋₆alkyl;    C₁₋₆alkyloxy optionally substituted with C₁₋₄alkyloxy;    C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy; C₁₋₆alkyloxy-carbonyl wherein    C₁₋₆alkyl may optionally be substituted with aryl; cyano;    aminocarbonyl; mono- or di(C₁₋₄alkyl)aminocarbonyl;    C₁₋₆alkylcarbonyl; nitro; amino; mono- or di(C₁₋₆alkyl)amino;    R⁴R³N—C₁₋₆alkyl; C₃₋₆cycloalkyl-NR^(x)—; aryl-NR^(x)—; Het-NR^(x)—;    C₃₋₆cycloalkylC₁₋₄alkyl-NR^(x)—; arylC₁₋₄alkyl-NR^(x)—;    HetC₁₋₄alkyl-NR^(x)—; —S(═O)_(p)—C₁₋₄alkyl; C₃₋₆cycloalkyl;    C₃₋₆cycloalkylC₁₋₄alkyl; C₃₋₆cycloalkyl-C(═O)—; aryl; aryloxy;    arylC₁₋₄alkyl; aryl-C(═O)—C₁₋₄alkyl; aryl-C(═O)—; Het; HetC₁₋₄alkyl;    Het-C(═O)—C₁₋₄alkyl; Het-C(═O)—; Het-O—;-   p represents 1 or 2;    a N-oxide thereof, a pharmaceutically acceptable salt thereof or a    solvate thereof;    or-   d) a compound having the formula

including any stereochemically isomeric form thereof, wherein

-   A represents CH or N;    the dotted line represents an optional bond in case A represents a    carbon atom;-   X represents —C(═O)—; —O—C(═O)—; —C(═O)—C(═O)—; —NR^(x)—C(═O)—;    —Z¹—C(═O)—; —Z¹—NR^(x)—C(═O)—; —C(═O)—Z¹—; —NR^(x)—C(═O)—Z¹—;    —S(═O)_(p)—; —C(═S)—; —NR^(x)—C(═S)—; —Z¹—C(═S)—; —Z¹—NR^(x)—C(═S)—;    —C(═S)—Z¹—; —NR^(x)—C(═S)—Z¹—;-   Z¹ represents a bivalent radical selected from C₁₋₆alkanediyl,    C₂₋₆alkenediyl or C₂₋₆alkynediyl; wherein each of said    C₁₋₆alkanediyl, C₂₋₆alkenediyl or C₂₋₆alkynediyl may optionally be    substituted with hydroxyl or amino; and wherein two hydrogen atoms    attached to the same carbon atom in C₁₋₆alkanediyl may optionally be    replaced by C₁₋₆alkanediyl;-   Y represents NR^(x)—C(═O)—Z²—; —NR^(x)—C(═O)—Z²—NR^(y)—;    —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—; —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—O—;    —NR^(x)—C(═O)—Z²—O—; —NR^(x)—C(═O)—Z²—O—C(═O)—;    —NR^(x)—C(═O)—Z²—C(═O)—; —NR^(x)—C(═O)—Z²—C(═O)—O—;    —NR^(x)—C(═O)—O—Z²—C(═O)—; —NR^(x)—C(═O)—O—Z²—C(═O)—O—;    —NR^(x)—C(═O)—O—Z²—O—C(═O)—; —NR^(x)—C(═O)—Z²—C(═O)—NR^(y)—;    —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—NR^(y)—; —C(═O)—Z²—; —C(═O)—Z²—O—;    —C(═O)—NR^(x)—Z²—; —C(═O)—NR^(x)—Z²—O—; —C(═O)—NR^(x)—Z²—C(═O)—O—;    —C(═O)—NR^(x)—Z²—O—C(═O)—; —C(═O)—NR^(x)—O—Z²—;    —C(═O)—NR^(x)—Z²—NR^(y)—; —C(═O)—NR^(x)—Z²—NR^(y)—C(═O)—;    —C(═O)—NR^(x)—Z²—NR^(y)—C(═O)—O—;-   Z² represents a bivalent radical selected from C₁₋₆alkanediyl,    C₂₋₆alkenediyl or C₂₋₆alkynediyl; wherein each of said    C₁₋₆alkanediyl, C₂₋₆alkenediyl or C₂₋₆alkynediyl may optionally be    substituted with C₁₋₄alkyloxy, C₁₋₄alkylthio, hydroxyl, cyano or    aryl; and wherein two hydrogen atoms attached to the same carbon    atom in the definition of Z² may optionally be replaced by    C₁₋₆alkanediyl;-   R^(x) represents hydrogen or C₁₋₄alkyl;-   R^(y) represents hydrogen; C₁₋₄alkyl optionally substituted with    C₃₋₆cycloalkyl or aryl or Het; C₂₋₄alkenyl; or —S(═O)_(p)-aryl;-   R¹ represents C₁₋₁₂alkyl optionally substituted with cyano,    C₁₋₄alkyloxy, C₁₋₄alkyl-oxyC₁₋₄alkyloxy, C₃₋₆cycloalkyl or aryl;    C₂₋₆alkenyl; C₂₋₆alkynyl; C₃₋₆cycloalkyl; adamantanyl; aryl¹;    aryl¹C₁₋₆alkyl; Het¹; or Het¹C₁₋₆alkyl; provided that when Y    represents —NR^(x)—C(═O)—Z²—; —NR^(x)—C(═O)—Z²—NR^(y);    —NR^(x)—C(═O)—Z²—C(═O)—NR^(y)—; —C(═O)—Z²—;    —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—NR^(y)—; —C(═O)—NR^(x)—Z²—;    —C(═O)—NR^(x)—O—Z²—; or —C(═O)—NR^(x)—Z²—NR^(y)—; then R¹ may also    represent hydrogen;-   R² represents hydrogen, C₁₋₁₂alkyl, C₂₋₆alkenyl or R³;-   R³ represents C₃₋₆cycloalkyl, phenyl, naphtalenyl,    2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl,    2,3-dihydrobenzofuranyl or a 6-membered aromatic heterocycle    containing 1 or 2 N atoms, wherein said C₃₋₆cycloalkyl, phenyl,    naphtalenyl, 2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl or    6-membered aromatic heterocycle containing 1 or 2 N atoms may    optionally be substituted with at least one substituent, in    particular one, two, three, four or five substituents, each    substituent independently selected from hydroxyl; carboxyl; halo;    C₁₋₆alkyl optionally substituted with hydroxy; polyhaloC₁₋₆alkyl;    C₁₋₆alkyloxy optionally substituted with C₁₋₄alkyloxy;    C₁₋₆alkylthio; polyhalo-C₁₋₆alkyloxy; C₁₋₆alkyloxycarbonyl wherein    C₁₋₆alkyl may optionally be substituted with aryl; cyano;    C₁₋₆alkylcarbonyl; nitro; amino; mono- or di(C₁₋₄alkyl)amino;    C₁₋₄alkylcarbonylamino; —S(═O)_(p)—C₁₋₄alkyl; R⁵R⁴N—C(═O)—;    R⁵R⁴N—C₁₋₆alkyl; C₃₋₆cycloalkyl; C₃₋₆cycloalkylC₁₋₄alkyl;    C₃₋₆cycloalkyl-C(═O)—; aryl; aryloxy; arylC₁₋₄alkyl;    aryl-C(═O)—C₁₋₄alkyl; aryl-C(═O)—; Het; HetC₁₋₄alkyl;    Het-C(═O)—C₁₋₄alkyl; Het-C(═O)—; Het-O—;-   R⁴ represents hydrogen; C₁₋₄alkyl optionally substituted with    hydroxyl or C₁₋₄alkyloxy; R⁷R⁶N—C₁₋₄alkyl; C₁₋₄alkyloxy; Het;    Het-C₁₋₄alkyl; aryl; R⁷R⁶N—C(═O)—C₁₋₄alkyl;-   R⁵ represents hydrogen or C₁₋₄alkyl;-   R⁶ represents hydrogen; C₁₋₄alkyl; C₁₋₄alkylcarbonyl;-   R⁷ represents hydrogen or C₁₋₄alkyl; or-   R⁶ and R⁷ may be taken together with the nitrogen to which they are    attached to form a saturated monocyclic 5, 6 or 7-membered    heterocycle which may further contain one or more heteroatoms each    independently selected from O, S, S(═O)_(p) or N; and which    heterocycle may optionally be substituted with C₁₋₄alkyl;-   R⁸ represents hydrogen, halo, C₁₋₄alkyl, C₁₋₄alkyl substituted with    hydroxyl;-   aryl represents phenyl or phenyl substituted with at least one    substituent, in particular one, two, three, four or five    substituents, each substituent independently being selected from    hydroxyl; carboxyl; halo; C₁₋₆alkyl optionally substituted with    C₁₋₄alkyloxy, amino or mono- or di(C₁₋₄alkyl)amino;    polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted with    C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy;    C₁₋₆alkyloxycarbonyl; cyano; aminocarbonyl; mono- or    di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono-    or di(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl;-   aryl¹ represents phenyl, naphthalenyl or fluorenyl; each of said    phenyl, naphthalenyl or fluorenyl optionally substituted with at    least one substituent, in particular one, two, three, four or five    substituents, each substituent independently being selected from    hydroxyl; oxo; carboxyl; halo; C₁₋₆alkyl optionally substituted with    carboxyl, C₁₋₄alkyloxycarbonyl or aryl-C(═O)—; hydroxyC₁₋₆alkyl    optionally substituted with aryl or aryl-C(═O)—; polyhaloC₁₋₆alkyl;    C₁₋₆alkyloxy optionally substituted with C₁₋₄alkyloxy;    C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy; C₁₋₆alkyloxy-carbonyl wherein    C₁₋₆alkyl may optionally be substituted with aryl; cyano;    aminocarbonyl; mono- or di(C₁₋₄alkyl)aminocarbonyl;    C₁₋₆alkylcarbonyl; nitro; amino; mono- or di(C₁₋₆alkyl)amino;    R⁵R⁴N—C₁₋₆alkyl; C₃₋₆cycloalkyl-NR^(x)—; aryl-NR^(x)—; Het-NR^(x)—;    C₃₋₆cycloalkylC₁₋₄alkyl-NR^(x)—; arylC₁₋₄alkyl-NR^(x)—;    HetC₁₋₄alkyl-NR^(x)—; —S(═O)_(p)—C₁₋₄alkyl; C₃₋₆cycloalkyl;    C₃₋₆cycloalkylC₁₋₄alkyl; C₃₋₆cycloalkyl-C(═O)—; aryl; aryloxy;    arylC₁₋₄alkyl; aryl-C(═O)—C₁₋₄alkyl; aryl-C(═O)—; Het; HetC₁₋₄alkyl;    Het-C(═O)—C₁₋₄alkyl; Het-C(═O)—; Het-O—;-   Het represents a monocyclic non-aromatic or aromatic heterocycle    containing at least one heteroatom each independently selected from    O, S, S(═O)_(p) or N; or a bicyclic or tricyclic non-aromatic or    aromatic heterocycle containing at least one heteroatom each    independently selected from O, S, S(═O)_(p) or N; said monocyclic    heterocycle or said bi- or tricyclic heterocycle optionally being    substituted with at least one substituent, in particular one, two,    three, four or five substituents, each substituent independently    being selected from hydroxyl; oxo; carboxyl; halo; C₁₋₆alkyl    optionally substituted with C₁₋₄alkyloxy, amino or mono- or    di(C₁₋₄alkyl)amino; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally    substituted with C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy;    C₁₋₆alkyloxycarbonyl; cyano; aminocarbonyl; mono- or    di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono-    or di(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl;-   Het¹ represents a monocyclic non-aromatic or aromatic heterocycle    containing at least one heteroatom each independently selected from    O, S, S(═O)_(p) or N; or a bicyclic or tricyclic non-aromatic or    aromatic heterocycle containing at least one heteroatom each    independently selected from O, S, S(═O)_(p) or N; said monocyclic    heterocycle or said bi- or tricyclic heterocycle optionally being    substituted with at least one substituent, in particular one, two,    three, four or five substituents, each substituent independently    being selected from hydroxyl; oxo; carboxyl; halo; C₁₋₆alkyl    optionally substituted with carboxyl, C₁₋₄alkyloxycarbonyl or    aryl-C(═O)—; hydroxyC₁₋₆alkyl optionally substituted with aryl or    aryl-C(═O)—; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted    with C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy;    C₁₋₆alkyloxy-carbonyl wherein C₁₋₆alkyl may optionally be    substituted with aryl; cyano; aminocarbonyl; mono- or    di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono-    or di(C₁₋₆alkyl)amino; R⁵R⁴N—C₁₋₆alkyl; C₃₋₆cycloalkyl-NR^(x)—;    aryl-NR^(x)—; Het-NR^(x)—; C₃₋₆cycloalkylC₁₋₄alkyl-NR^(x)—;    arylC₁₋₄alkyl-NR^(x)—; HetC₁₋₄alkyl-NR^(x)—; —S(═O)_(p)—C₁₋₄alkyl;    C₃₋₆cycloalkyl; C₃₋₆cycloalkylC₁₋₄alkyl; C₃₋₆cycloalkyl-C(═O)—;    aryl; aryloxy; arylC₁₋₄alkyl; aryl-C(═O)—C₁₋₄alkyl; aryl-C(═O)—;    Het; HetC₁₋₄alkyl; Het-C(═O)—C₁₋₄alkyl; Het-C(═O)—; Het-O—;-   p represents 1 or 2;-   provided that if X represents —O—C(═O)—, then R² represents R³;    a N-oxide thereof, a pharmaceutically acceptable salt thereof or a    solvate thereof.

Hereinafter, the compounds of formula (I) as defined under a) areindicated as class A compounds, the compounds as defined under b) areindicated as class B compounds, the compounds as defined under c) areindicated as class C compounds, and the compounds as defined under d)are indicated as class D compounds.

In an embodiment, the present invention relates to combinations of aDGAT inhibitor wherein the DGAT inhibitor is selected from

-   a) a compound of class A, class B, class C, or class D;    and-   b) a PPAR-α agonist or a prodrug thereof.

In an embodiment, the present invention relates to combinations of aDGAT inhibitor wherein the DGAT inhibitor is selected from

-   a) a compound of class A, class B, class C, or class D;    and-   b) a fibrate.

In an embodiment, the present invention relates to combinations of aDGAT inhibitor wherein the DGAT inhibitor is selected from

-   a) a compound of class A, class B, class C, or class D;    and-   b) fenofibrate.

In an embodiment, the present invention relates to any of the precedingembodiments wherein the DGAT inhibitor is selected from a compound ofClass A.

In an embodiment, the present invention relates to any of the precedingembodiments wherein the DGAT inhibitor is selected from a compound ofClass B.

In an embodiment, the present invention relates to any of the precedingembodiments wherein the DGAT inhibitor is selected from a compound ofClass C.

In an embodiment, the present invention relates to any of the precedingembodiments wherein the DGAT inhibitor is selected from a compound ofClass D.

In an embodiment, the present invention relates to any of the precedingor the following embodiments wherein the PPAR agonist or a prodrugthereof, is a PPAR-α agonist or a prodrug thereof, more in particular afibrate, even more in particular a fenofibrate.

In an embodiment, the present invention relates to any of the precedingor following embodiments wherein the DGAT inhibitor is a DGAT1inhibitor.

The present invention also concerns methods for the preparation ofcompounds of class A, class B, class C or class D, and combinations orpharmaceutical compositions comprising them.

The combinations according to the present invention are suitable for useas a medicament.

The combinations according to the present invention are suitable forreducing food intake, for reducing weight, for suppressing appetite, forinducing satiety; or for the treatment or prevention, in particulartreatment, of metabolic disorders, such as obesity and/or obesityrelated disorders (including, but not limited to, peripheral vasculardisease, cardiac failure, myocardial ischaemia, cerebral ischaemia,cardiac myopathies), diabetes, in particular type II diabetes mellitus,and/or complications arising therefrom (such as retinopathy, neuropathy,nephropathy), syndrome X, insulin resistance, impaired glucosetolerance, conditions of impaired fasting glucose, hypoglycemia,hyperglycemia, hyperuricemia, hyperinsulinemia, pancreatitis,hypercholesterolemia, hyperlipidemia, dyslipidemia, mixed dyslipidemia,hypertriglyceridemia, nonalcoholic fatty liver disease, fatty liver,increased mesenteric fat, non-alcoholic steatohepatitis, liver fibrosis,metabolic acidosis, ketosis, dysmetabolic syndrome; dermatologicalconditions such as acne, psoriasis; cardiovascular diseases, such asatherosclerosis, arteriosclerosis, acute heart failure, congestive heartfailure, coronary artery disease, cardiomyopathy, myocardial infarction,angina pectoris, hypertension, hypotension, stroke, ischemia, ischemicreperfusion injury, aneurysm, restenosis or vascular stenosis;alzheimer's disease; neoplastic diseases, such as solid tumors, skincancer, melanoma, lymphoma or endothelial cancers, e.g., breast cancer,lung cancer, colorectal cancer, stomach cancer, other cancers of thegastrointestinal tract (e.g., esophageal cancer or pancreatic cancer),prostate cancer, kidney cancer, liver cancer, bladder cancer, cervicalcancer, uterine cancer, testicular cancer or ovarian cancer.

The combinations according to the present invention are particularlysuitable for the treatment of prevention, in particular treatment, ofobesity, type II diabetes mellitus; for suppressing appetite, forinducing satiety and/or for reducing food intake.

The present invention also relates to the use of the combinationsaccording to the present invention for the manufacture of a medicamentfor the treatment or prevention, in particular treatment, of the abovementioned diseases or conditions.

The present invention also relates to the use of a combination of a DGATinhibitor, in particular a DGAT1 inhibitor, and a PPAR agonist or aprodrug thereof, in particular a PPAR-α agonist or a prodrug thereof,more in particular a fibrate, even more in particular fenofibrate, forthe manufacture of a medicament for the prevention or the treatment, inparticular for the treatment, of a disease which can benefit fromelevated levels of one or more satiety hormones, in particular GLP-1.

The present invention also relates to a product containing a) a DGATinhibitor, in particular a DGAT1 inhibitor, more in particular acompound of Class A, Class B, Class C or Class D, and (b) an agonist ofperoxisome proliferators-activator receptor such as for examplefenofibrate, as a combined preparation for simultaneous, separate orsequential use in the treatment of a disease which can benefit from anelevated level of GLP-1 or DGAT inhibition, such as for examplediabetes, in particular type II diabetes mellitus, obesity, forsuppressing appetite, inducing satiety or for reducing food intake.

In an embodiment, the present invention also relates to pharmaceuticalcompositions comprising a pharmaceutically acceptable carrier, and asactive ingredient a therapeutically effective amount of the combinationsmentioned hereinbefore or hereinafter.

The present invention further relates to novel compounds, wherein thecompound is selected from:

-   N-[4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]phenyl]-4-methoxy-benzeneacetamide    (compound 355 Class D);-   4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide    (compound 151 Class C);-   4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide    (compound 354 Class D);-   4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]hydroxyacetyl]-1-piperazinyl]-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide    (compound 356 Class D);-   4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]hydroxyacetyl]-1-piperazinyl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide    (compound 152 Class C);-   4-[4-[[2,6-dichloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide    (compound 358 Class D);-   4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide    (compound 353 Class D);-   4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]hydroxyacetyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide    (compound 357 Class D);-   4-[4-[[2,6-dichloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide    (compound 147 Class C);-   4-[4-[[2,6-dichloro-4-[(4-ethyl-1-piperazinyl)methyl]phenyl]acetyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide    (compound 360 Class D);-   4-[4-[[2,6-dichloro-4-[(4-ethyl-1-piperazinyl)methyl]phenyl]acetyl]-1-piperazinyl]-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide    (compound 359 Class D);-   4-[4-[[2,6-dichloro-4-[[4-(methylsulfonyl)-1-piperazinyl]methyl]phenyl]acetyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide    (compound 364 Class D);-   4-[4-[[4-[(4-acetyl-1-piperazinyl)methyl]-2,6-dichlorophenyl]acetyl]-1-piperazinyl]-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide    (compound 361 Class D);-   4-[4-[[2,6-dichloro-4-[[4-(methylsulfonyl)-1-piperazinyl]methyl]phenyl]acetyl]-1-piperazinyl]-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide    (compound 363 Class D);-   4-[4-[[4-[(4-acetyl-1-piperazinyl)methyl]-2,6-dichlorophenyl]acetyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide    (compound 362 Class D);-   4-[4-[[2,6-dichloro-4-[[4-(methylsulfonyl)-1-piperazinyl]methyl]phenyl]acetyl]-1-piperazinyl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide    (compound 150 Class C);-   4-[4-[[4-[(4-acetyl-1-piperazinyl)methyl]-2,6-dichlorophenyl]acetyl]-1-piperazinyl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide    (compound 149 Class C);-   4-[4-[[2,6-dichloro-4-[(4-ethyl-1-piperazinyl)methyl]phenyl]acetyl]-1-piperazinyl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide    (compound 148 Class C);    including any stereochemically isomeric forms thereof;    N-oxides thereof, pharmaceutically acceptable salts thereof or    solvates thereof.

Hereinafter, the novel compounds as defined in the list hereabove(compounds 147 till 152 from Class C, and compounds 353 till 364 fromClass D; including any stereochemically isomeric forms thereof; N-oxidesthereof, pharmaceutically acceptable salts thereof or solvates thereof),are indicated as compounds of group Q.

The present invention further relates to the novel compound4-[4-[[2,6-dichloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide(compound 358 Class D); including any stereochemically isomeric formsthereof; N-oxides thereof, pharmaceutically acceptable salts thereof orsolvates thereof.

The present invention also relates to a compound of group Q for use as amedicament.

The present invention also relates to a compound of group Q for theprevention or the treatment of a disease mediated by DGAT, in particularthe present invention relates to a compound of group Q for theprevention or the treatment of a disease which can benefit frominhibition of DGAT, in particular for the treatment of a disease whichcan benefit from inhibition of DGAT, in particular DGAT1.

The present invention also relates to a compound of group Q for theprevention or the treatment, in particular for the treatment, of adisease which can benefit from elevated levels of one or more satietyhormones, in particular GLP-1.

The present invention also relates to the use of a compound of group Qfor the manufacture of a medicament for the treatment or prevention, inparticular treatment, of the above mentioned diseases or conditions.

In an embodiment, the present invention also relates to pharmaceuticalcompositions comprising a pharmaceutically acceptable carrier, and asactive ingredient a therapeutically effective amount of a compound ofgroup Q.

The present invention will now be further described. In the followingpassages, different aspects of the invention are defined in more detail.

DETAILED DESCRIPTION

All terms used are to be construed in accordance with the followingdefinitions, unless the context indicates otherwise. In general, theterms are valid for the compounds of class A, class B, class C and classD, unless it is indicated that a certain definition for a term is onlyvalid for a certain class or subset of classes.

As used hereinbefore or hereinafter C₀₋₃alkyl as a group or part of agroup defines straight or branched chain saturated hydrocarbon radicalshaving from 0 (then it represents a direct bond) to 3 carbon atoms suchas methyl, ethyl, propyl, 1-methylethyl; C₁₋₂alkyl as a group or part ofa group defines straight or branched chain saturated hydrocarbonradicals having 1 or 2 carbon atoms such as methyl, ethyl;

C₁₋₄alkyl as a group or part of a group defines straight or branchedchain saturated hydrocarbon radicals having from 1 to 4 carbon atomssuch as methyl, ethyl, propyl, 1-methylethyl, butyl; C₁₋₅alkyl as agroup or part of a group defines straight or branched chain saturatedhydrocarbon radicals having from 1 to 5 carbon atoms such as the groupdefined for C₁₋₄alkyl and pentyl, 2-methylbutyl and the like; C₁₋₆alkylas a group or part of a group defines straight or branched chainsaturated hydrocarbon radicals having rom 1 to 6 carbon atoms such asthe group defined for C₁₋₄alkyl and for C₁₋₅alkyl and hexyl,2-methylpentyl and the like; C₁₋₁₂alkyl as a group or part of a groupdefines straight or branched chain saturated hydrocarbon radicals havingfrom 1 to 12 carbon atoms such as the group defined for C₁₋₆alkyl andheptyl, 2-methylheptyl and the like; C₁₋₆alkanediyl defines straight orbranched chain saturated bivalent hydrocarbon radicals having from 1 to6 carbon atoms such as methylene, 1,2-ethanediyl or 1,2-ethylidene,1,3-propanediyl or 1,3-propylidene, 1,4-butanediyl or 1,4-butylidene,1,5-pentanediyl and the like; C₂₋₄alkenyl as a group or part of a groupdefines straight or branched chain hydrocarbon radicals having from 2 to4 carbon atoms and having a double bond such as ethenyl, propenyl,butenyl and the like; C₂₋₆alkenyl as a group or part of a group definesstraight or branched chain hydrocarbon radicals having from 2 to 6carbon atoms and having a double bond such as the group defined forC₂₋₄alkenyl and pentenyl, hexenyl, 3-methylbutenyl and the like;C₂₋₆alkenediyl defines straight or branched chain bivalent hydrocarbonradicals having from 2 to 6 carbon atoms and having a double bond suchas 1,2-ethenediyl, 1,3-propenediyl, 1,4-butenediyl, 1,5-pentenediyl andthe like; C₂₋₆alkynyl defines straight and branched chain hydrocarbonradicals having from 2 to 6 carbon atoms and having a triple bond suchas ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like;C₂₋₆alkynediyl as a group or part of a group defines straight orbranched chain bivalent hydrocarbon radicals having from 2 to 6 carbonatoms and having a triple bond such as 1,2-ethynediyl, 1,3-propynediyl,1,4-butynediyl, 1,5-pentynediyl and the like; C₃₋₆cycloalkyl is genericto cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term halo is generic to fluoro, chloro, bromo and iodo. As usedhereinbefore or hereinafter, polyhaloC₁₋₆alkyl as a group or part of agroup is defined as C₁₋₆alkyl substituted with one or more, such as forexample 2, 3, 4 or 5 halo atoms, for example methyl substituted with oneor more fluoro atoms, for example, difluoromethyl or trifluoromethyl,1,1-difluoro-ethyl, 1,1-difluoro-2,2,2-trifluoro-ethyl and the like. Incase more than one halogen atoms are attached to a C₁₋₆alkyl groupwithin the definition of polyhaloC₁₋₆alkyl, they may be the same ordifferent.

As used herein before, the term (═O) forms a carbonyl moiety whenattached to a carbon atom, a sulfoxide moiety when attached to a sulfuratom and a sulfonyl moiety when two of said terms are attached to asulfur atom. Oxo means ═O.

The radical R¹, as defined hereinabove for the compounds of class B, maybe an optionally substituted 5-membered monocyclic heterocyclecontaining at least 2 heteroatoms, an optionally substituted 6-memberedaromatic monocyclic heterocycle or an optionally substituted 5-memberedheterocycle containing at least 2 heteroatoms fused with a phenyl,cyclohexyl or a 5- or 6-membered heterocycle.

A 5-membered monocyclic heterocycle as defined hereinabove orhereinafter may be a 5-membered monocyclic non-aromatic (fully saturatedor partially saturated) or aromatic heterocycle containing at least 2heteroatom, in particular 2 or 3 heteroatoms, each independentlyselected from O, S, S(═O)_(p) or N. Examples of such unsubstitutedmonocyclic 5-membered heterocycles comprise, but are not limited to,non-aromatic (fully saturated or partially saturated) or aromatic5-membered monocyclic heterocycles such as for example 1,3-dioxolanyl,imidazolidinyl, thiazolidinyl, dihydrooxazolyl, isothiazolidinyl,isoxazolidinyl, oxadiazolidinyl, triazolidinyl, thiadiazolidinyl,pyrazolidinyl, imidazolinyl, pyrazolinyl, imidazolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, thiadiazolyl,oxadiazolyl, tetrazolyl and the like. Optional substituents of the aboveheterocycles are hydroxyl; oxo; carboxyl; halo; C₁₋₆alkyl optionallysubstituted with carboxyl, C₁₋₄alkyloxy-carbonyl or aryl-C(═O)—;hydroxyC₁₋₆alkyl optionally substituted with aryl or aryl-C(═O)—;polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted withC₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy; C₁₋₆alkyloxy-carbonylwherein C₁₋₆alkyl may optionally be substituted with aryl; cyano;aminocarbonyl; mono- or di(C₁₋₄alkyl)-aminocarbonyl; C₁₋₆alkylcarbonyl;amino; mono- or di(C₁₋₆alkyl)amino; R⁵R⁴N—C₁₋₆ alkyl;C₃₋₆cycloalkyl-NR^(x)—; aryl-NR^(x)—; Het-NR^(x)—;C₃₋₆cycloalkylC₁₋₄alkyl-NR^(x)—; arylC₁₋₄alkyl-NR^(x)—;HetC₁₋₄alkyl-NR^(x)—; —S(═O)_(p)—C₁₋₄alkyl; C₃₋₆cycloalkyl;C₃₋₆cycloalkylC₁₋₄alkyl; C₃₋₆cycloalkyl-C(═O)—; aryl; aryloxy;arylC₁₋₄alkyl; aryl-C(═O)—; aryl-C(═O)—C₁₋₄alkyl; Het; HetC₁₋₄alkyl;Het-C(═O)—; Het-C(═O)—C₁₋₄alkyl; Het-O—.

A 6-membered aromatic monocyclic heterocycle as defined hereinabove orhereinafter contains at least one heteroatom, in particular 1, 2 or 3heteroatoms, each independently selected from O, S, S(═O)_(p) or N.Examples of such unsubstituted monocyclic 6-membered aromaticheterocycles comprise, but are not limited to, pyridyl, pyrimidinyl,pyrazinyl, pyridazinyl, triazinyl, pyranyl and the like. Optionalsubstituents of the above heterocycles are hydroxyl; oxo; carboxyl;halo; C₁₋₆alkyl optionally substituted with carboxyl,C₁₋₄alkyloxycarbonyl or aryl-C(═O)—; hydroxyC₁₋₆alkyl optionallysubstituted with aryl or aryl-C(═O)—; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxyoptionally substituted with C₁₋₄alkyloxy; C₁₋₆alkylthio;polyhaloC₁₋₆alkyloxy; C₁₋₆alkyloxy-carbonyl wherein C₁₋₆alkyl mayoptionally be substituted with aryl; cyano; aminocarbonyl; mono- ordi(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; amino; mono- ordi(C₁₋₆alkyl)amino; R⁵R⁴N—C₁₋₆alkyl; C₃₋₆cycloalkyl-NR^(x)—;aryl-NR^(x)—; Het-NR^(x)—; C₃₋₆ cycloalkylC₁₋₄alkyl-NR^(x)—;arylC₁₋₄alkyl-NR^(x)—; HetC₁₋₄alkyl-NR^(x)—; —S(═O)_(p)—C₁₋₄alkyl;C₃₋₆cycloalkyl; C₃₋₆cycloalkylC₁₋₄alkyl; C₃₋₆cycloalkyl-C(═O)—; aryl;aryloxy; arylC₁₋₄alkyl; aryl-C(═O)—; aryl-C(═O)—C₁₋₄alkyl; Het;HetC₁₋₄alkyl; Het-C(═O)—; Het-C(═O)—C₁₋₄alkyl; Het-O—.

A 5-membered heterocycle containing at least 2 heteroatoms fused withphenyl, cyclohexyl or a 5- or 6-membered heterocycle as definedhereinabove or hereinafter may be a non-aromatic (fully saturated orpartially saturated) or aromatic 5-membered heterocycle containing atleast 2 heteroatoms, in particular 2 or 3 heteroatoms, eachindependently selected from O, S, S(═O)_(p) or N, in particular O, S orN, more in particular O or N, fused with phenyl, cyclohexyl or a 5- or6-membered non-aromatic (fully saturated or partially saturated) oraromatic heterocycle containing at least one heteroatom, in particular1, 2 or 3 heteroatoms, each independently selected from O, S, S(═O)_(p)or N. Examples of such unsubstituted bicyclic heterocycles comprise, butare not limited to, non-aromatic (fully saturated or partiallysaturated) or aromatic 8- or 9-membered bicyclic heterocycles such asfor example 1,3-benzodioxolyl, benzoxazolyl, benzimidazolyl, indazolyl,benzisoxazolyl, benzisothiazolyl, benzopyrazolyl, benzoxadiazolyl,benzothiadiazolyl, benzotriazolyl, purinyl, pyrrolopyridyl,thienopyridyl, furopyridyl, isothiazolopyridyl, thiazolopyridyl,isoxazolopyridyl, oxazolopyridyl, pyrazolopyridyl, imidazopyridyl,pyrrolopyrazinyl, thienopyrazinyl, furopyrazinyl, isothiazolopyrazinyl,thiazolopyrazinyl, isoxazolopyrazinyl, oxazolopyrazinyl,pyrazolopyrazinyl, imidazopyrazinyl, pyrrolopyrimidinyl,thienopyrimidinyl, furopyrimidinyl, isothiazolopyrimidinyl,thiazolopyrimidinyl, isoxazolopyrimidinyl, oxazolopyrimidinyl,pyrazolopyrimidinyl, imidazopyrimidinyl, pyrrolopyridazinyl,thienopyridazinyl, furopyridazinyl, isothiazolopyridazinyl,thiazolopyridazinyl, isoxazolopyridazinyl, oxazolopyridazinyl,pyrazolopyridazinyl, imidazopyridazinyl, oxadiazolopyridyl,thiadiazolopyridyl, triazolopyridyl, oxadiazolopyrazinyl,thiadiazolopyrazinyl, triazolopyrazinyl, oxadiazolopyrimidinyl,thiadiazolopyrimidinyl, triazolopyrimidinyl, oxadiazolopyridazinyl,thiadiazolopyridazinyl, triazolopyridazinyl, imidazooxazolyl,imidazothiazolyl, imidazoimidazolyl, imidazopyrazolyl,isoxazolotriazinyl, isothiazolotriazinyl, pyrazolotriazinyl,oxazolotriazinyl, thiazolotriazinyl, imidazotriazinyl,oxadiazolotriazinyl, thiadiazolotriazinyl, triazolotriazinyl and thelike. Optional substituents of the above heterocycles are hydroxyl; oxo;carboxyl; halo; C₁₋₆alkyl optionally substituted with carboxyl,C₁₋₄alkyloxycarbonyl or aryl-C(═O)—; hydroxyC₁₋₆alkyl optionallysubstituted with aryl or aryl-C(═O)—; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxyoptionally substituted with C₁₋₄alkyloxy; C₁₋₆alkylthio;polyhaloC₁₋₆alkyloxy; C₁₋₆alkyloxy-carbonyl wherein C₁₋₆alkyl mayoptionally be substituted with aryl; cyano; aminocarbonyl; mono- ordi(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; amino; mono- ordi(C₁₋₆alkyl)amino; R⁵R⁴N—C₁₋₆alkyl; C₃₋₆cycloalkyl-NR^(x)—;aryl-NR^(x)—; Het-NR^(x)—; C₃₋₆cycloalkylC₁₋₄alkyl-NR^(x)—;arylC₁₋₄alkyl-NR^(x)—; HetC₁₋₄alkyl-NR^(x)—; —S(═O)_(p)—C₁₋₄alkyl;C₃₋₆cycloalkyl; C₃₋₆cycloalkylC₁₋₄alkyl; C₃₋₆cycloalkyl-C(═O)—; aryl;aryloxy; arylC₁₋₄alkyl; aryl-C(═O)—; aryl-C(═O)—C₁₋₄alkyl; Het;HetC₁₋₄alkyl; Het-C(═O)—; Het-C(═O)—C₁₋₄alkyl; Het-O—.

The radical Het or Het¹ as defined hereinabove may be an optionallysubstituted monocyclic non-aromatic or aromatic heterocycle containingat least one heteroatom, in particular 1, 2 or 3 heteroatoms, eachindependently selected from O, S, S(═O)_(p) or N; or an optionallysubstituted bi- or tricyclic non-aromatic or aromatic heterocyclecontaining at least one heteroatom, in particular 1, 2, 3, 4 or 5heteroatoms, each independently selected from O, S, S(═O)_(p) or N.Examples of such unsubstituted monocyclic heterocycles comprise, but arenot limited to, non-aromatic (fully saturated or partially saturated) oraromatic 4-, 5-, 6- or 7-membered monocyclic heterocycles such as forexample azetidinyl, tetrahydrofuranyl, pyrrolidinyl, dioxolanyl,imidazolidinyl, thiazolidinyl, tetrahydrothienyl, dihydrooxazolyl,isothiazolidinyl, isoxazolidinyl, oxadiazolidinyl, triazolidinyl,thiadiazolidinyl, pyrazolidinyl, piperidinyl, hexahydropyrimidinyl,hexahydropyrazinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl,piperazinyl, trithianyl, hexahydrodiazepinyl, pyrrolinyl, imidazolinyl,pyrazolinyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl,thiazolyl, isothiazolyl, pyrazolyl, triazolyl, thiadiazolyl,oxadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,triazinyl, pyranyl and the like. Examples of such unsubstituted bicyclicor tricyclic heterocycles comprise, but are not limited to, non-aromatic(fully saturated or partially saturated) or aromatic 8- to 17-memberedbicyclic or tricyclic heterocycles such as for exampledecahydroquinolinyl, octahydroindolyl, 2,3-dihydrobenzofuranyl,1,3-benzodioxolyl, 2,3-dihydro-1,4-benzodioxinyl, indolinyl, benzofuryl,isobenzofuryl, benzothienyl, isobenzo-thienyl, indolizinyl, indolyl,isoindolyl, benzoxazolyl, benzimidazolyl, indazolyl, benzisoxazolyl,benzisothiazolyl, benzopyrazolyl, benzoxadiazolyl, benzothiadiazolyl,benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl,quinolizinyl, phthalazinyl, quinoxalinyl, quinazolinyl, naphthiridinyl,pteridinyl, benzopyranyl, pyrrolopyridyl, thienopyridyl, furopyridyl,isothiazolopyridyl, thiazolopyridyl, isoxazolopyridyl, oxazolopyridyl,pyrazolopyridyl, imidazopyridyl, pyrrolopyrazinyl, thienopyrazinyl,furopyrazinyl, isothiazolopyrazinyl, thiazolopyrazinyl,isoxazolopyrazinyl, oxazolo-pyrazinyl, pyrazolopyrazinyl,imidazopyrazinyl, pyrrolopyrimidinyl, thienopyrimidinyl,furopyrimidinyl, isothiazolopyrimidinyl, thiazolopyrimidinyl,isoxazolopyrimidinyl, oxazolopyrimidinyl, pyrazolopyrimidinyl,imidazopyrimidinyl, pyrrolopyridazinyl, thienopyridazinyl,furopyridazinyl, isothiazolopyridazinyl, thiazolopyridazinyl,isoxazolopyridazinyl, oxazolopyridazinyl, pyrazolopyridazinyl,imidazopyridazinyl, oxadiazolopyridyl, thiadiazolopyridyl,triazolopyridyl, oxadiazolopyrazinyl, thiadiazolopyrazinyl,triazolopyrazinyl, oxadiazolopyrimidinyl, thiadiazolopyrimidinyl,triazolopyrimidinyl, oxadiazolopyridazinyl, thiadiazolopyridazinyl,triazolopyridazinyl, imidazooxazolyl, imidazothiazolyl,imidazoimidazolyl, imidazopyrazolyl; isoxazolotriazinyl,isothiazolotriazinyl, pyrazolotriazinyl, oxazolotriazinyl,thiazolotriazinyl, imidazotriazinyl, oxadiazolotriazinyl,thiadiazolotriazinyl, triazolotriazinyl, carbazolyl, acridinyl,phenazinyl, phenothiazinyl, phenoxazinyl and the like. Optionalsubstituents for Het heterocycles are hydroxyl; oxo; carboxyl; halo;C₁₋₆alkyl optionally substituted with C₁₋₄alkyloxy, amino or mono- ordi(C₁₋₄alkyl)amino; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionallysubstituted with C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy;C₁₋₆alkyl-oxycarbonyl; cyano; aminocarbonyl; mono- ordi(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono- ordi(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl. Optional substituents for Het¹substituents are hydroxyl; oxo; carboxyl; halo; C₁₋₆alkyl optionallysubstituted with carboxyl, C₁₋₄alkyloxycarbonyl or aryl-C(═O)—;hydroxyC₁₋₆alkyl optionally substituted with aryl or aryl-C(═O)—;polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted withC₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy; C₁₋₆alkyloxy-carbonylwherein C₁₋₆alkyl may optionally be substituted with aryl; cyano;aminocarbonyl; mono- or di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl;amino; mono- or di(C₁₋₆alkyl)amino; R⁶R⁵N—C₁₋₆alkyl;C₃₋₆cycloalkyl-NR^(x)—; aryl-NR^(x)—; Het-NR^(x)—;C₃₋₆cycloalkylC₁₋₄alkyl-NR^(x)—; arylC₁₋₄alkyl-NR^(x)—;HetC₁₋₄alkyl-NR^(x)—; —S(═O)_(p)—C₁₋₄alkyl; C₃₋₆cycloalkyl;C₃₋₆cycloalkylC₁₋₄alkyl; C₃₋₆cycloalkyl-C(═O)—; aryl; aryloxy;arylC₁₋₄alkyl; aryl-C(═O)—; aryl-C(═O)—C₁₋₄alkyl; Het; HetC₁₋₄alkyl;Het-C(═O)—; Het-C(═O)—C₁₋₄alkyl; Het-O—.

Examples of a 6-membered aromatic heterocycle containing 1 or 2 N atomsin the definition of R³ (class B and class D) and R² (class C) arepyridyl, pyrimidinyl, pyridazinyl, pyrazinyl.

When any variable occurs more than one time in any constituent (e.g.aryl, Het), each definition is independent.

The term Het or Het¹ is meant to include all the possible isomeric formsof the heterocycles, for instance, pyrrolyl comprises 1H-pyrrolyl and2H-pyrrolyl.

The term R¹ (in class B) is meant to include all the possible isomericforms of the heterocycles, for instance, pyrrolyl comprises 1H-pyrrolyland 2H-pyrrolyl.

The carbocycles or heterocycles covered by the terms aryl, Het, aryl¹,Het¹, R¹ (in class B) or R³ (in class B, class C or class D) may beattached to the remainder of the molecule of formula (I) of class A,class B, class C or class D through any ring carbon or heteroatom asappropriate, if not otherwise specified. Thus, for example, when theheterocycle is imidazolyl, it may be 1-imidazolyl, 2-imidazolyl,4-imidazolyl and the like, or when the carbocycle is naphthalenyl, itmay be 1-naphthalenyl, 2-naphthalenyl and the like.

Lines drawn from substituents into ring systems indicate that the bondmay be attached to any of the suitable ring atoms.

When X is defined as for instance —NR^(x)—C(═O)—, this means that thenitrogen of NR^(x) is linked to the R² substituent (not applicable forclass A) and the carbon atom of C(═O) is linked to the nitrogen of thering

Thus the left part of the bivalent radical in the definition of X islinked to the R² substituent and the right part of the bivalent radicalin the definition of X is linked to the ring moiety

When Y is defined for instance as —NR^(x)—C(═O)— in class A or class C,this means that the nitrogen of NR^(x) is linked to the phenyl moietyand the carbon atom of C(═O) is linked to the R¹ substituent. Thus theleft part of the bivalent radical in the definition of Y is linked tothe phenyl moiety and the right part of the bivalent radical in thedefinition of Y is linked to the R¹ substituent.

When Y is defined as for instance —NR^(x)—C(═O)—Z²— in class D, thismeans that the nitrogen of NR^(x) is linked to the phenyl ring and theZ² is linked to the R¹ substituent. Thus the left part of the bivalentradical in the definition of Y is linked to the phenyl ring and theright part of the bivalent radical in the definition of Y is linked toR¹ substituent.

Some of the compounds of class A, class B, class C or class D may alsoexist in their tautomeric form. Such forms although not explicitlyindicated in the above formula are intended to be included within thescope of the present invention.

Whenever used hereinbefore or hereinafter that substituents can beselected each independently out of a list of numerous definitions, suchas for example for R² and R³ in class A, R⁴ and R⁵ in class B and classD, and R³ and R⁴ in class C, all possible combinations are intendedwhich are chemically possible.

For therapeutic use, salts of the compounds of class A, class B, class Cor class D are those wherein the counterion is pharmaceuticallyacceptable. However, salts of acids and bases which arenon-pharmaceutically acceptable may also find use, for example, in thepreparation or purification of a pharmaceutically acceptable compound.All salts, whether pharmaceutically acceptable or not are includedwithin the ambit of the present invention.

The pharmaceutically acceptable salts as mentioned hereinbefore orhereinafter are meant to comprise the therapeutically active non-toxicacid addition salt forms which the compounds of class A, class B, classC or class D are able to form. The latter can conveniently be obtainedby treating the base form with such appropriate acids as inorganicacids, for example, hydrohalic acids, e.g. hydrochloric, hydrobromic andthe like; sulfuric acid; nitric acid; phosphoric acid and the like; ororganic acids, for example, acetic, propanoic, hydroxyacetic,2-hydroxypropanoic, 2-oxopropanoic, oxalic, malonic, succinic, maleic,fumaric, malic, tartaric, 2-hydroxy-1,2,3-propanetricarboxylic,methanesulfonic, ethanesulfonic, benzenesulfonic,4-methylbenzenesulfonic, cyclohexanesulfonic, 2-hydroxybenzoic,4-amino-2-hydroxybenzoic and the like acids. Conversely the salt formcan be converted by treatment with alkali into the free base form.

The compounds of class A, class B, class C or class D containing acidicprotons may be converted into their therapeutically active non-toxicmetal or amine addition salt forms by treatment with appropriate organicand inorganic bases. The pharmaceutically acceptable salts as mentionedhereinbefore or hereinafter are meant to also comprise thetherapeutically active non-toxic metal or amine addition salt forms(base addition salt forms) which the compounds of class A, class B,class C or class D are able to form. Appropriate base addition saltforms comprise, for example, the ammonium salts, the alkali and earthalkaline metal salts, e.g. the lithium, sodium, potassium, magnesium,calcium salts and the like, salts with organic bases, e.g. primary,secondary and tertiary aliphatic and aromatic amines such asmethylamine, ethylamine, propylamine, isopropylamine, the fourbutylamine isomers, dimethylamine, diethylamine, diethanolamine,dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine,piperidine, morpholine, trimethylamine, triethylamine, tripropylamine,quinuclidine, pyridine, quinoline and isoquinoline, the benzathine,N-methyl-D-glucamine, 2-amino-2-(hydroxymethyl)-1,3-propanediol,hydrabamine salts, and salts with amino acids such as, for example,arginine, lysine and the like.

Conversely the salt form can be converted by treatment with acid intothe free acid form.

The term salt also comprises the quaternary ammonium salts (quaternaryamines) which the compounds of class A, class B, class C or class D areable to form by reaction between a basic nitrogen of a compound of classA, class B, class C or class D and an appropriate quaternizing agent,such as, for example, an optionally substituted C₁₋₆alkylhalide,arylhalide, C₁₋₆alkyl-carbonylhalide, arylcarbonylhalide, orarylC₁₋₆alkylhalide, e.g. methyliodide or benzyliodide. Other reactantswith good leaving groups may also be used, such as for example C₁₋₆alkyltrifluoromethanesulfonates, C₁₋₆alkyl methanesulfonates, and C₁₋₆alkylp-toluenesulfonates. A quaternary amine has a positively chargednitrogen. Pharmaceutically acceptable counterions include chloro, bromo,iodo, trifluoroacetate, acetate, triflate, sulfate, sulfonate. Thecounterion of choice can be introduced using ion exchange resins.

The term solvate comprises the hydrates and solvent addition forms whichthe compounds of class A, class B, class C or class D are able to form,as well as salts thereof. Examples of such forms are e.g. hydrates,alcoholates and the like.

The N-oxide forms of the present compounds are meant to comprise thecompounds of class A, class B, class C or class D wherein one or severaltertiary nitrogen atoms are oxidized to the so-called N-oxide.

It will be appreciated that some of the compounds of class A, class B,class C or class D may contain one or more centers of chirality andexist as stereochemically isomeric forms.

The term “stereochemically isomeric forms” as used hereinbefore orhereinafter defines all the possible stereoisomeric forms which thecompounds of class A, class B, class C or class D may possess. Unlessotherwise mentioned or indicated, the chemical designation of compoundsdenotes the mixture of all possible stereochemically isomeric forms,said mixtures containing all diastereomers and enantiomers of the basicmolecular structure as well as each of the individual isomeric forms ofthe basis molecular structure and their N-oxides, salts or solvates,substantially free, i.e. associated with less than 10%, preferably lessthan 5%, in particular less than 2% and most preferably less than 1% ofthe other isomers. Thus, when a compound of class A, class B, class C orclass D is for instance specified as (E), this means that the compoundis substantially free of the (Z) isomer.

In particular, stereogenic centers may have the R- or S-configuration;substituents on bivalent cyclic (partially) saturated radicals may haveeither the cis- or trans-configuration. Compounds encompassing doublebonds can have an E (entgegen) or Z (zusammen)-stereochemistry at saiddouble bond. The terms cis, trans, R, S, E and Z are well known to aperson skilled in the art.

Stereochemically isomeric forms of the compounds of class A, class B,class C or class D are obviously intended to be embraced within thescope of this invention.

Following CAS-nomenclature conventions, when two stereogenic centers ofknown absolute configuration are present in a molecule, an R or Sdescriptor is assigned (based on Cahn-Ingold-Prelog sequence rule) tothe lowest-numbered chiral center, the reference center. Theconfiguration of the second stereogenic center is indicated usingrelative descriptors [R*,R*] or [R*,S*], where the first R* is alwaysspecified as the reference center and [R*,R*] indicates centers with thesame chirality and [R*,S*] indicates centers of unlike chirality. Forexample, if the lowest-numbered chiral center in the molecule has an Sconfiguration and the second center is R, the stereo descriptor would bespecified as S-[R*,S*]. If “α” and “β” are used: the position of thehighest priority substituent on the asymmetric carbon atom in the ringsystem having the lowest ring number, is arbitrarily always in the “α”position of the mean plane determined by the ring system. The positionof the highest priority substituent on the other asymmetric carbon atomin the ring system relative to the position of the highest prioritysubstituent on the reference atom is denominated “α”, if it is on thesame side of the mean plane determined by the ring system, or “β”, if itis on the other side of the mean plane determined by the ring system.

The compounds of (I) may be synthesized in the form of racemic mixturesof enantiomers which can be separated from one another followingart-known resolution procedures. The racemic compounds of class A, classB, class C or class D may be converted into the correspondingdiastereomeric salt forms by reaction with a suitable chiral acid. Saiddiastereomeric salt forms are subsequently separated, for example, byselective or fractional crystallization and the enantiomers areliberated therefrom by alkali. An alternative manner of separating theenantiomeric forms of the compounds of class A, class B, class C orclass D involves liquid chromatography using a chiral stationary phase.Said pure stereochemically isomeric forms may also be derived from thecorresponding pure stereochemically isomeric forms of the appropriatestarting materials, provided that the reaction occursstereospecifically. Preferably if a specific stereoisomer is desired,said compound will be synthesized by stereospecific methods ofpreparation. These methods will advantageously employ enantiomericallypure starting materials.

Whenever used hereinbefore or hereinafter, the term “compounds of classA”, “compounds of class B”, “compounds of class C” or “compounds ofclass D” or any subgroup thereof, is meant to also include their N-oxideforms, their salts, their stereochemically isomeric forms and theirsolvates. Of special interest are those compounds of class A, class B,class C or class D which are stereochemically pure.

Whenever used hereinbefore or hereinafter, the term “compounds of groupQ”, is meant to also include their N-oxide forms, their salts, theirstereochemically isomeric forms and their solvates. Of special interestare those compounds group Q which are stereochemically pure.

By PPAR agonist, in particular PPAR-α agonist, is meant a compound or aprodrug thereof, or a composition containing said compound or prodrugthereof; which directly or indirectly stimulates or increases an in vivoor in vitro reaction typical for the PPAR receptor, in particular thePPAR-α receptor, e.g. transcriptional regulation activity, as measuredby an assay known to one skilled in the art such as, for example,described in Kuwabara K, Murakami K, Todo M, Aoki T, Asaki T, Mura M,and Yano J (2004) A novel selective peroxisome proliferator-activatedreceptor α agonist,2-methyl-c-5-[4-[5-methyl-2-(4-methylphenyl)-4-oxazolyl]butyl]-1,3-dioxane-r-2-carboxylicacid (NS-220), potently decreases plasma triglyceride and glucose levelsand modifies lipoprotein profiles in KK-A^(y) mice. J Pharmacol Exp TherVol. 309, No. 3: 970-977.

Non-limiting examples of PPAR-α agonists or prodrugs thereof includenatural and synthetic agonists, such as eicosanoids, leukotriene β₄,carbaprostacyclin, nonsteroidal anti-inflammatory drugs, pirinixic acid(WY-14643; PPAR-α/γ agonist), phthalate ester plasticizers,pterostilbene, fibrates or active metabolites thereof, α-substitutedphenyl-propanoic acid derivatives, isoxazolyl-serine-based compounds.

A preferred PPAR-α agonist or a prodrug thereof is a fibrate compoundincluding, but not limited to fenofibrate (fenofibric acid as activemetabolite), bezafibrate, clofibrate, ciprofibrate, etofibrate, ABT-335(which is the choline salt of fenofibric acid), pirifibrate,beclofibrate or gemfibrozil (a PPAR-α modulator) and analogues,derivatives and pharmaceutically acceptable salts thereof.

Whenever the term ‘prodrug’ is used within the context of thisinvention, this refers to a pharmacological substance (drug) that isadministered in an inactive or significantly less active form. Onceadministered, the prodrug is metabolised in vivo into an activemetabolite. For example, the prodrug fenofibrate (ester) is metabolisedto fenofibric acid which is the active metabolite (PPAR-α agonist).

A preferred fibrate is fenofibrate.

In the present invention, fibrates include fibric acid derivatives andpharmaceutically acceptable salts of such fibric acid derivatives.

The next embodiments of the present invention are those combinations ofa DGAT inhibitor, more in particular a DGAT1 inhibitor and a PPARagonist, in particular a PPAR-α agonist, more in particular a fibrate,even more in particular fenofibrate; wherein the DGAT inhibitor isselected from compounds of Class A. Preferred embodiments of compoundsof class A are:

-   A-1) compounds of class A having the following formula (I)

including any stereochemically isomeric form thereof, wherein

-   A represents CH or N;-   X represents O or NR^(x);-   the dotted line represents an optional bond in case A represents a    carbon atom;-   Y represents a direct bond; —NR^(x)—C(═O)—; —C(═O)—NR^(x)—;    —NR^(x)—C(═O)—Z—; —NR^(x)—C(═O)—Z—NR^(y)—;    —NR^(x)—C(═O)—Z—NR^(y)—C(═O)—; —NR^(x)—C(═O)—Z—NR^(y)—C(═O)—O—;    —NR^(x)—C(═O)—Z—O—; —NR^(x)—C(═O)—Z—O—C(═O)—;    —NR^(x)—C(═O)—Z—C(═O)—; —NR^(x)—C(═O)—Z—C(═O)—O—;    —NR^(x)—C(═O)—O—Z—C(═O)—; —NR^(x)—C(═O)—O—Z—C(═O)—O—;    —NR^(x)—C(═O)—O—Z—O—C(═O)—; —NR^(x)—C(═O)—Z—C(═O)—NR^(y)—;    —NR^(x)—C(═O)—Z—NR^(y)—C(═O)—NR^(y)—; —C(═O)—Z—; —C(═O)—Z—O—;    —C(═O)—NR^(x)—Z—; —C(═O)—NR^(x)—Z—O—; —C(═O)—NR^(x)—Z—C(═O)—O—;    —C(═O)—NR^(x)—Z—O—C(═O)—; —C(═O)—NR^(x)—O—Z—;    —C(═O)—NR^(x)—Z—NR^(y)—; —C(═O)—NR^(x)—Z—NR^(y)—C(═O)—;    —C(═O)—NR^(x)—Z—NR^(y)—C(═O)—O—;-   Z represents a bivalent radical selected from C₁₋₆alkanediyl,    C₂₋₆alkenediyl or C₂₋₆alkynediyl; wherein each of said    C₁₋₆alkanediyl, C₂₋₆alkenediyl or C₂₋₆alkynediyl may optionally be    substituted with C₁₋₄alkyloxy, C₁₋₄alkylthio, hydroxyl, cyano or    aryl; and wherein two hydrogen atoms attached to the same carbon    atom in the definition of Z may optionally be replaced by    C₁₋₆alkanediyl;-   R^(x) represents hydrogen or C₁₋₄alkyl;-   R^(y) represents hydrogen; C₁₋₄alkyl optionally substituted with    C₃₋₆cycloalkyl or aryl or Het; C₂₋₄alkenyl; or —S(═O)_(p)-aryl;-   R¹ represents C₁₋₁₂alkyl optionally substituted with cyano,    C₁₋₄alkyloxy, C₁₋₄alkyl-oxyC₁₋₄alkyloxy, C₃₋₆cycloalkyl or aryl;    C₂₋₆alkenyl; C₂₋₆alkynyl; C₃₋₆cycloalkyl; aryl¹; aryl¹C₁₋₆alkyl;    Het¹; or Het¹C₁₋₆alkyl; provided that when Y represents    —NR^(x)—C(═O)—Z—; —NR^(x)—C(═O)—Z—NR^(y);    —NR^(x)—C(═O)—Z—C(═O)—NR^(y)—; —C(═O)—Z—;    —NR^(x)—C(═O)—Z—NR^(y)—C(═O)—NR^(y)—; —C(═O)—NR^(x)—Z—;    —C(═O)—NR^(x)—O—Z—; or —C(═O)—NR^(x)—Z—NR^(y)—; then R¹ may also    represent hydrogen;-   R² and R³ each independently represent hydrogen; hydroxyl; carboxyl;    halo; C₁₋₆alkyl; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally    substituted with C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy;    C₁₋₆alkyloxycarbonyl; cyano; aminocarbonyl; mono- or    di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono-    or di(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl;-   R⁴ represents hydrogen; hydroxyl; carboxyl; halo; C₁₋₆alkyl;    polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted with    C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhalo-C₁₋₆alkyloxy;    C₁₋₆alkyloxycarbonyl wherein C₁₋₆alkyl may optionally be substituted    with aryl; cyano; C₁₋₆alkylcarbonyl; nitro; amino; mono- or    di(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl; R⁶R⁵N—C(═O)—;    R⁶R⁵N—C₁₋₆alkyl; C₃₋₆cycloalkyl; aryl; aryloxy; arylC₁₋₄alkyl;    aryl-C(═O)—; Het; HetC₁₋₄alkyl; Het-C(═O)—; Het-O—;-   R⁵ represents hydrogen; C₁₋₄alkyl optionally substituted with    hydroxyl or C₁₋₄alkyloxy; R⁸R⁷N—C₁₋₄alkyl; C₁₋₄alkyloxy; Het; aryl;    R⁸R⁷N—C(═O)—C₁₋₄alkyl;-   R⁶ represents hydrogen or C₁₋₄alkyl;-   R⁷ represents hydrogen; C₁₋₄alkyl; C₁₋₄alkylcarbonyl;-   R⁸ represents hydrogen or C₁₋₄alkyl; or-   R⁷ and R⁸ may be taken together with the nitrogen to which they are    attached to form a saturated monocyclic 5, 6 or 7-membered    heterocycle which may further contain one or more heteroatoms    selected from O, S, S(═O)_(p) or N; and which heterocycle may    optionally be substituted with C₁₋₄alkyl;-   aryl represents phenyl or phenyl substituted with at least one    substituent, in particular one, two, three, four or five    substituents, each substituent independently being selected from    hydroxyl; carboxyl; halo; C₁₋₆alkyl optionally substituted with    C₁₋₄alkyloxy, amino or mono- or di(C₁₋₄alkyl)amino;    polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted with    C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy;    C₁₋₆alkyloxycarbonyl; cyano; aminocarbonyl; mono- or    di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono-    or di(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl;-   aryl¹ represents phenyl, naphthalenyl or fluorenyl; each of said    phenyl, naphthalenyl or fluorenyl optionally substituted with at    least one substituent, in particular one, two, three, four or five    substituents, each substituent independently being selected from    hydroxyl; oxo; carboxyl; halo; C₁₋₆alkyl optionally substituted with    aryl-C(═O)—; hydroxyC₁₋₆alkyl optionally substituted with aryl or    aryl-C(═O)—; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted    with C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy;    C₁₋₆alkyloxy-carbonyl wherein C₁₋₆alkyl may optionally be    substituted with aryl; cyano; aminocarbonyl; mono- or    di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono-    or di(C₁₋₆alkyl)amino; C₃₋₆cycloalkyl-NR^(x)—; aryl-NR^(x)—;    Het-NR^(x)—; C₃₋₆cycloalkylC₁₋₄alkyl-NR⁸—; arylC₁₋₄alkyl-NR^(x)—;    HetC₁₋₄alkyl-NR^(x)—; —S(═O)_(p)—C₁₋₄alkyl; C₃₋₆cycloalkyl;    C₃₋₆cycloalkylC₁₋₄alkyl; C₃₋₆cycloalkyl-C(═O)—; aryl; aryloxy;    arylC₁₋₄alkyl; aryl-C(═O)—; Het; HetC₁₋₄alkyl; Het-C(═O)—; Het-O—;-   Het represents a monocyclic non-aromatic or aromatic heterocycle    containing at least one heteroatom selected from O, S, S(═O)_(p) or    N; or a bicyclic or tricyclic non-aromatic or aromatic heterocycle    containing at least one heteroatom selected from O, S, S(═O)_(p) or    N; said monocyclic heterocycle or said bi- or tricyclic heterocycle    optionally being substituted with at least one substituent, in    particular one, two, three, four or five substituents, each    substituent independently being selected from hydroxyl; oxo;    carboxyl; halo; C₁₋₆alkyl optionally substituted with C₁₋₄alkyloxy,    amino or mono- or di(C₁₋₄alkyl)amino; polyhaloC₁₋₆alkyl;    C₁₋₆alkyloxy optionally substituted with C₁₋₄alkyloxy;    C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy; C₁₋₆alkyl-oxycarbonyl; cyano;    aminocarbonyl; mono- or di(C₁₋₄alkyl)aminocarbonyl;    C₁₋₆alkylcarbonyl; nitro; amino; mono- or di(C₁₋₄alkyl)amino;    —S(═O)_(p)—C₁₋₄alkyl;-   Het¹ represents a monocyclic non-aromatic or aromatic heterocycle    containing at least one heteroatom selected from O, S, S(═O)_(p) or    N; or a bicyclic or tricyclic non-aromatic or aromatic heterocycle    containing at least one heteroatom selected from O, S, S(═O)_(p) or    N; said monocyclic heterocycle or said bi- or tricyclic heterocycle    optionally being substituted with at least one substituent, in    particular one, two, three, four or five substituents, each    substituent independently being selected from hydroxyl; oxo;    carboxyl; halo; C₁₋₆alkyl optionally substituted with aryl-C(═O)—;    hydroxyC₁₋₆alkyl optionally substituted with aryl or aryl-C(═O)—;    polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted with    C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy;    C₁₋₆alkyloxy-carbonyl wherein C₁₋₆alkyl may optionally be    substituted with aryl; cyano; aminocarbonyl; mono- or    di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono-    or di(C₁₋₆alkyl)amino; C₃₋₆cycloalkyl-NR^(x)—; aryl-NR^(x)—;    Het-NR^(x)—; C₃₋₆cycloalkylC₁₋₄alkyl-NR^(x)—; arylC₁₋₄alkyl-NR^(x)—;    HetC₁₋₄alkyl-NR^(x)—; —S(═O)_(p)—C₁₋₄alkyl; C₃₋₆cycloalkyl;    C₃₋₆cycloalkylC₁₋₄alkyl; C₃₋₆cycloalkyl-C(═O)—; aryl; aryloxy;    arylC₁₋₄alkyl; aryl-C(═O)—; Het; HetC₁₋₄alkyl; Het-C(═O)—; Het-O—;-   p represents 1 or 2;-   a N-oxide thereof, a pharmaceutically acceptable salt thereof or a    solvate thereof;    or-   A-2) compounds of class A or any subgroup thereof as mentioned    hereinbefore as embodiment, wherein X represents NR^(x), in    particular NH;    or-   A-3) compounds of class A or, whenever possible, any subgroup    thereof as mentioned hereinbefore as embodiment, wherein X    represents O;    or-   A-4) compounds of class A or, whenever possible, any subgroup    thereof as mentioned hereinbefore as embodiment wherein A represents    N;    or-   A-5) compounds of class A or, whenever possible, any subgroup    thereof as mentioned hereinbefore as embodiment wherein A represents    CH, in particular wherein A represents CH and the dotted line does    not represent a bond;    or-   A-6) compounds of class A or any subgroup thereof as mentioned    hereinbefore as embodiment wherein Y represents    —NR^(x)—C(═O)—; —NR^(x)—C(═O)—Z—, —NR^(x)—C(═O)—Z—NR^(y)—;    —NR^(x)—C(═O)—Z—O—C(═O)—; in particular wherein Y represents    —NR^(x)—C(═O)— or —NR^(x)—C(═O)—Z— with Z representing    C₁₋₆alkanediyl;    or-   A-7) compounds of class A or, whenever possible, any subgroup    thereof as mentioned hereinbefore as embodiment wherein Y represents    a direct bond, in particular wherein Y represents a direct bond and    R¹ represents Het¹;    or-   A-8) compounds of class A or, whenever possible, any subgroup    thereof as mentioned hereinbefore as embodiment wherein Y represents    —NR^(x)—C(═O)—, in particular wherein Y represents —NR^(x)—C(═O)—    and R¹ represents Aryl¹ or Het¹;    or-   A-9) compounds of class A or, whenever possible, any subgroup    thereof as mentioned hereinbefore as embodiment wherein Y represents    —NR^(x)—C(═O)—Z—NR^(y)—, in particular wherein Y represents    —NR^(x)—C(═O)—Z—NR^(y)— and R¹ represents Aryl¹ or Het¹;    or-   A-10) compounds of class A or, whenever possible, any subgroup    thereof as mentioned hereinbefore as embodiment wherein Y represents    —NR^(x)—C(═O)—Z—C(═O)—O— or —NR^(x)—C(═O)—Z—O—C(═O)—, in particular    —NR^(x)—C(═O)—Z—O—C(═O)—;    or-   A-11) compounds of class A or, whenever possible, any subgroup    thereof as mentioned hereinbefore as embodiment wherein R² or R³    each independently represent hydrogen, halo or C₁₋₆alkyl, in    particular both R² and R³ represent halo, more in particular both R²    and R³ represent chloro or fluoro;    or-   A-12) compounds of class A or, whenever possible, any subgroup    thereof as mentioned hereinbefore as embodiment wherein R⁴ is placed    in para position;    or-   A-13) compounds of class A or, whenever possible, any subgroup    thereof as mentioned hereinbefore as embodiment wherein R⁴    represents hydrogen; carboxyl; C₁₋₆alkyloxycarbonyl; amino; mono- or    di(C₁₋₄alkyl)amino; R⁶R⁵N—C(═O)—; R⁶R⁵N—C₁₋₆alkyl; Het-C(═O)— or    HetC₁₋₄alkyl, in particular Het-C(═O)— or HetC₁₋₄alkyl;    or-   A-14) compounds of class A or, whenever possible, any subgroup    thereof as mentioned hereinbefore as embodiment wherein R⁴ is placed    in para position and represents hydrogen; carboxyl;    C₁₋₆alkyloxy-carbonyl; amino; mono- or di(C₁₋₄alkyl)amino;    R⁶R⁵N—C(═O)—; R⁶R⁵N—C₁₋₆alkyl; Het-C(═O)— or HetC₁₋₄alkyl, in    particular Het-C(═O)— or HetC₁₋₄alkyl;    or-   A-15) compounds of class A or, whenever possible, any subgroup    thereof as mentioned hereinbefore as embodiment wherein p represents    2;    or-   A-16) compounds of class A or, whenever possible, any subgroup    thereof as mentioned hereinbefore as embodiment wherein R¹    represents hydrogen; C₁₋₁₂alkyl; aryl¹ or Het¹; in particular Aryl¹    or Het¹; more in particular Aryl¹; more in particular optionally    substituted phenyl wherein the optional substituent is preferably    selected from aryl, Het or C₁₋₆alkyloxy; even more in particular    phenyl;    or-   A-17) compounds of class A or, whenever possible, any subgroup    thereof as mentioned hereinbefore as embodiment wherein Z represents    C₁₋₆alkanediyl;    or-   A-18) compounds of class A or, whenever possible, any subgroup    thereof as mentioned hereinbefore as embodiment wherein R^(x)    represents hydrogen;    or-   A-19) compounds of class A or, whenever possible, any subgroup    thereof as mentioned hereinbefore as embodiment wherein R^(y)    represents hydrogen;    or-   A-20) compounds of class A or, whenever possible, any subgroup    thereof as mentioned hereinbefore as embodiment wherein R⁹    represents hydrogen;    or-   A-21) compounds of class A or, whenever possible, any subgroup    thereof as mentioned hereinbefore as embodiment wherein R⁹    represents halo, C₁₋₄alkyl, C₁₋₄alkyl substituted with hydroxyl;    or-   A-22) compounds of class A or any subgroup thereof as mentioned    hereinbefore as embodiment wherein one or more, preferably all, of    the following restrictions apply:-   a) X represents NH;-   b) R² represents hydrogen, halo or C₁₋₆alkyl; in particular halo;    more in paticular chloro;-   c) R³ represents hydrogen, halo or C₁₋₆alkyl; in particular halo;    more in particular chloro;-   d) R⁴ represents hydrogen;-   e) A represents N;-   f) the dotted line does not represent an additional bond;-   g) Y represents —NR^(x)—C(═O)—Z—;-   h) Z represents C₁₋₆alkanediyl;-   i) R¹ represents aryl¹; in particular optionally substituted phenyl;    more in particular phenyl.-   j) R^(x) represents hydrogen;    or-   A-23) compounds of class A or any subgroup thereof as mentioned    hereinbefore as embodiment wherein one or more, preferably all, of    the following restrictions apply:-   a) X represents NH or O;-   b) R² represents hydrogen, halo or C₁₋₆alkyl; in particular halo;    more in particular chloro or fluoro;-   c) R³ represents hydrogen, halo or C₁₋₆alkyl; in particular halo;    more in particular chloro or fluoro;-   d) R⁴ represents hydrogen; carboxyl; C₁₋₆alkyloxycarbonyl;    Het-C(═O)— or HetC₁₋₄alkyl, in particular Het-C(═O)— or    HetC₁₋₄alkyl;-   e) A represents N;-   f) the dotted line does not represent a bond;-   g) Y represents —NR^(x)—C(═O)—; —NR^(x)—C(═O)—Z—,    —NR^(x)—C(═O)—Z—NR^(y)—; —NR^(x)—C(═O)—Z—O—C(═O)—;-   h) Z represents C₁₋₆alkanediyl;-   i) R¹ represents hydrogen; C₁₋₁₂alkyl; aryl¹ or Het¹; in particular    aryl¹; more in particular optionally substituted phenyl wherein the    optional substituent is preferably selected from aryl, Het or    C₁₋₆alkyloxy; more in particular phenyl;-   j) R^(x) represents hydrogen;-   k) R^(y) represents hydrogen;-   l) R⁹ represents hydrogen;-   m) R⁴ is placed in para position;    or-   A-24) compounds of class A selected from

including any stereochemically isomeric form thereof;

-   a N-oxide thereof, a pharmaceutically acceptable salt thereof or a    solvate thereof.

The next embodiments of the present invention are those combinations ofa DGAT inhibitor, more in particular a DGAT1 inhibitor and a PPARagonist, in particular a PPAR-α agonist, more in particular a fibrate,even more in particular fenofibrate; wherein the DGAT inhibitor isselected from compounds of Class B. Preferred embodiments of compoundsof class B are:

-   B-1) compounds of class B having the following formula (I)

including any stereochemically isomeric form thereof, wherein

-   A represents CH or N;-   the dotted line represents an optional bond in case A represents a    carbon atom;-   X represents —NR^(x)—C(═O)—; —Z—C(═O)—; —Z—NR^(x)—C(═O)—;    —S(═O)_(p)—; —C(═S)—; —NR^(x)—C(═S)—; —Z—C(═S)—; —Z—NR^(x)—C(═S)—;-   Z represents a bivalent radical selected from C₁₋₆alkanediyl,    C₂₋₆alkenediyl or C₂₋₆alkynediyl; wherein each of said    C₁₋₆alkanediyl, C₂₋₆alkenediyl or C₂₋₆alkynediyl may optionally be    substituted with hydroxyl;-   R^(x) represents hydrogen or C₁₋₄alkyl;-   R¹ represents a 5-membered monocyclic heterocycle containing at    least 2 heteroatoms; a 6-membered aromatic monocyclic heterocycle;    or a 5-membered heterocycle containing at least 2 heteroatoms fused    with phenyl, cyclohexyl or a 5- or 6-membered heterocycle; wherein    each of said heterocycles may optionally be substituted with at    least one substituent, in particular one, two, three, four or five    substituents, each substituent independently being selected from    hydroxyl; oxo; carboxyl; halo; C₁₋₆alkyl optionally substituted with    aryl-C(═O)—; hydroxyC₁₋₆alkyl optionally substituted with aryl or    aryl-C(═O)—; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted    with C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy;    C₁₋₆alkyloxy-carbonyl wherein C₁₋₆alkyl may optionally be    substituted with aryl; cyano; aminocarbonyl; mono- or    di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono-    or di(C₁₋₆alkyl)amino; C₃₋₆cycloalkyl-NR^(x)—; aryl-NR^(x)—;    Het-NR^(x)—; C₃₋₆cycloalkylC₁₋₄alkyl-NR^(x)—; arylC₁₋₄alkyl-NR^(x)—;    HetC₁₋₄alkyl-NR^(x)—; —S(═O)_(p)—C₁₋₄alkyl; C₃₋₆cycloalkyl;    C₃₋₆cycloalkylC₁₋₄alkyl; C₃₋₆cycloalkyl-C(═O)—; aryl; aryloxy;    arylC₁₋₄alkyl; aryl-C(═O)—; Het; HetC₁₋₄alkyl; Het-C(═O)—; Het-O—;-   R² represents R³;-   R³ represents C₃₋₆cycloalkyl, phenyl, naphtalenyl,    2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl, wherein said    C₃₋₆cycloalkyl, phenyl, naphtalenyl, 2,3-dihydro-1,4-benzodioxinyl,    1,3-benzodioxolyl may optionally be substituted with at least one    substituent, in particular one, two, three, four or five    substituents, each substituent independently selected from hydroxyl;    carboxyl; halo; C₁₋₆alkyl optionally substituted with hydroxy;    polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted with    C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhalo-C₁₋₆alkyloxy;    C₁₋₆alkyloxy-carbonyl wherein C₁₋₆alkyl may optionally be    substituted with aryl; cyano; C₁₋₆alkylcarbonyl; nitro; amino; mono-    or di(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl; R⁵R⁴N—C(═O)—;    R⁵R⁴N—C₁₋₆alkyl; C₃₋₆cycloalkyl; C₃₋₆cycloalkylC₁₋₄alkyl;    C₃₋₆cycloalkyl-C(═O)—; aryl; aryloxy; arylC₁₋₄alkyl; aryl-C(═O)—;    Het; HetC₁₋₄alkyl; Het-C(═O)—; Het-O—;-   R⁴ represents hydrogen; C₁₋₄alkyl optionally substituted with    hydroxyl or C₁₋₄alkyloxy; R⁷R⁶N—C₁₋₄alkyl; C₁₋₄alkyloxy; Het; aryl;    R⁷R⁶N—C(═O)—C₁₋₄alkyl;-   R⁵ represents hydrogen or C₁₋₄alkyl;-   R⁶ represents hydrogen; C₁₋₄alkyl; C₁₋₄alkylcarbonyl;-   R⁷ represents hydrogen or C₁₋₄alkyl; or-   R⁶ and R⁷ may be taken together with the nitrogen to which they are    attached to form a saturated monocyclic 5, 6 or 7-membered    heterocycle which may further contain one or more heteroatoms    selected from O, S, S(═O)_(p) or N; and which heterocycle may    optionally be substituted with C₁₋₄alkyl;-   aryl represents phenyl or phenyl substituted with at least one    substituent, in particular one, two, three, four or five    substituents, each substituent independently being selected from    hydroxyl; carboxyl; halo; C₁₋₆alkyl optionally substituted with    C₁₋₄alkyloxy, amino or mono- or di(C₁₋₄alkyl)amino;    polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted with    C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy;    C₁₋₆alkyloxycarbonyl; cyano; aminocarbonyl; mono- or    di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono-    or di(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl;-   Het represents a monocyclic non-aromatic or aromatic heterocycle    containing at least one heteroatom selected from O, S, S(═O)_(p) or    N; or a bicyclic or tricyclic non-aromatic or aromatic heterocycle    containing at least one heteroatom selected from O, S, S(═O)_(p) or    N; said monocyclic heterocycle or said bi- or tricyclic heterocycle    optionally being substituted with at least one substituent, in    particular one, two, three, four or five substituents, each    substituent independently being selected from hydroxyl; oxo;    carboxyl; halo; C₁₋₆alkyl optionally substituted with C₁₋₄alkyloxy,    amino or mono- or di(C₁₋₄alkyl)amino; polyhaloC₁₋₆alkyl;    C₁₋₆alkyloxy optionally substituted with C₁₋₄alkyloxy;    C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy; C₁₋₆alkyl-oxycarbonyl; cyano;    aminocarbonyl; mono- or di(C₁₋₄alkyl)aminocarbonyl;    C₁₋₆alkylcarbonyl; nitro; amino; mono- or di(C₁₋₄alkyl)amino;    —S(═O)_(p)—C₁₋₄alkyl;-   p represents 1 or 2;-   a N-oxide thereof, a pharmaceutically acceptable salt thereof or a    solvate thereof;    or-   B-2) compounds of class B or, whenever possible, any subgroup    thereof as mentioned hereinbefore as embodiment wherein X represents    —NR^(x)—C(═O)—; —Z—C(═O)—; —Z—NR^(x)—C(═O)—; —S(═O)_(p)—;    —NR^(x)—C(═S)— or —O—C(═O)—; in particular X represents    —NR^(x)—C(═O)—; —Z—C(═O)—; —Z—NR^(x)—C(═O)—; more in particular X    represents —NR^(x)—C(═O)— or —Z—C(═O)—;    or-   B-3) compounds of class B or, whenever possible, any subgroup    thereof as mentioned hereinbefore as embodiment wherein A represents    N;    or-   B-4) compounds of class B or, whenever possible, any subgroup    thereof as mentioned hereinbefore as embodiment wherein A represents    CH, in particular wherein A represents CH and the dotted line does    not represent a bond;    or-   B-5) compounds of class B or, whenever possible, any subgroup    thereof as mentioned hereinbefore as embodiment wherein R¹    represents a 5-membered monocyclic heterocycle containing at least 2    heteroatoms, in particular pyrazolyl, triazolyl or oxadiazolyl; a    6-membered monocyclic aromatic heterocycle, in particular    pyrimidinyl; or a 5-membered aromatic heterocycle containing at    least 2 heteroatoms fused with a 5-membered heterocycle, in    particular imidazopyrazolyl or imidazothiazolyl; wherein each of    said heterocycles may optionally be substituted, preferably with one    or two substituents. Particular substituents of said heterocycles    include oxo, C₁₋₆alkyl optionally substituted with aryl-C(═O)— or    C₁₋₄alkyloxycarbonyl; hydroxyC₁₋₆alkyl optionally substituted with    aryl or aryl-C(═O)—; amino; mono- or di(C₁₋₆alkyl)amino;    R⁵R⁴N—C₁₋₆alkyl; C₃₋₆cycloalkyl-NR^(x)—; aryl-NR^(x)—; Het-NR^(x)—;    C₃₋₆cycloalkylC₁₋₄alkyl-NR^(x)—; arylC₁₋₄alkyl-NR^(x)—;    HetC₁₋₄alkyl-NR^(x)—; C₃₋₆cycloalkyl; C₃₋₆cycloalkylC₁₋₄alkyl; aryl;    aryloxy; arylC₁₋₄alkyl; aryl-C(═O)—; aryl-C(═O)—C₁₋₄alkyl; Het;    HetC₁₋₄alkyl; Het-C(═O)—; Het-C(═O)—C₁₋₄alkyl; Het-O—; more in    particular C₁₋₆alkyl optionally substituted with aryl-C(═O)— or    C₁₋₄alkyloxycarbonyl; hydroxyC₁₋₆alkyl optionally substituted with    aryl; mono- or di(C₁₋₆alkyl)amino; R⁵R⁴N—C₁₋₆alkyl;    C₃₋₆cycloalkyl-NR^(x)—; Het-NR^(x)—; arylC₁₋₄alkyl-NR^(x)—;    C₃₋₆cycloalkyl; C₃₋₆cycloalkylC₁₋₄alkyl; aryl; arylC₁₋₄alkyl;    aryl-C(═O)—C₁₋₄alkyl or Het;    or-   B-6) compounds of class B or, whenever possible, any subgroup    thereof as mentioned hereinbefore as embodiment wherein the compound    of class B is a compound of formula (I′)

wherein R^(3a) and R^(3b) each independently represent hydrogen;hydroxyl; carboxyl; halo; C₁₋₆alkyl optionally substituted withhydroxyl; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted withC₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy; C₁₋₆alkyloxycarbonyl;cyano; aminocarbonyl; mono- or di(C₁₋₄alkyl)aminocarbonyl;C₁₋₆alkylcarbonyl; nitro; amino; mono- or di(C₁₋₄alkyl)amino;C₁₋₄alkylcarbonylamino; —S(═O)_(p)—C₁₋₄alkyl; and wherein R^(3a)represents hydrogen; hydroxyl; carboxyl; halo; C₁₋₆alkyl;polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted withC₁₋₄alkyloxy; C₁₋₆alkylthio; polyhalo-C₁₋₆alkyloxy; C₁₋₆alkyloxycarbonylwherein C₁₋₆alkyl may optionally be substituted with aryl; cyano;C₁₋₆alkylcarbonyl; nitro; amino; mono- or di(C₁₋₄alkyl)amino;—S(═O)_(p)—C₁₋₄alkyl; R⁵R⁴N—C(═O)—; R⁵R⁴N—C₁₋₆alkyl; C₃₋₆cyclo-alkyl;aryl; aryloxy; arylC₁₋₄alkyl; aryl-C(═O)—; Het; HetC₁₋₄alkyl;Het-C(═O)—; Het-O—.or

-   B-7) compounds of class B or, whenever possible, any subgroup    thereof as mentioned hereinbefore as embodiment wherein the compound    of class B is a compound of formula (I″)

wherein R^(3a) and R^(3b) each independently represent hydrogen;hydroxyl; carboxyl; halo; C₁₋₆alkyl; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxyoptionally substituted with C₁₋₄alkyloxy; C₁₋₆alkylthio;polyhaloC₁₋₆alkyloxy; C₁₋₆alkyloxycarbonyl; cyano; aminocarbonyl; mono-or di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono- ordi(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl; and wherein R^(3c) representshydrogen; hydroxyl; carboxyl; halo; C₁₋₆alkyl optionally substitutedwith hydroxyl; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substitutedwith C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhalo-C₁₋₆alkyl-oxy;C₁₋₆alkyloxycarbonyl wherein C₁₋₆alkyl may optionally be substitutedwith aryl; cyano; C₁₋₆alkylcarbonyl; nitro; amino; mono- ordi(C₁₋₄alkyl)amino; C₁₋₄alkylcarbonyl-amino; —S(═O)_(p)—C₁₋₄alkyl;R⁵R⁴N—C(═O)—; R⁵R⁴N—C₁₋₆alkyl; C₃₋₆cycloalkyl; aryl; aryloxy;arylC₁₋₄alkyl; aryl-C(═O)—; Het; HetC₁₋₄alkyl; Het-C(═O)—; Het-O—;or

-   B-8) compounds of class B or, whenever possible, any subgroup    thereof as mentioned hereinbefore as embodiment wherein the compound    of formula (I) is a compound of formula (I′) or (I″) and wherein    R^(3a) and R^(3b) each independently represent halo,    polyhaloC₁₋₆alkyl, C₁₋₆alkyl or C₁₋₆alkyloxy, in particular both    R^(3a) and R^(3b) represent halo, more in particular both R^(3a) and    R^(3b) represent chloro;    or-   B-9) compounds of class B or, whenever possible, any subgroup    thereof as mentioned hereinbefore as embodiment wherein the compound    of class B is a compound of formula (I′) or (I″) and wherein R^(3c)    represents hydrogen, hydroxyl, carboxyl; halo; amino; mono- or    di-(C₁₋₄alkyl)amino; C₁₋₆alkyl; C₁₋₆alkyloxy; C₁₋₆alkyloxycarbonyl;    C₁₋₆alkylthio; C₁₋₄alkylcarbonylamino; R⁵R⁴N—C(═O)—;    R⁵R⁴N—C₁₋₆alkyl; Het-C(═O)— or HetC₁₋₄alkyl; or R^(3c) represents    hydrogen;    or-   B-10) compounds of class B or, whenever possible, any subgroup    thereof as mentioned hereinbefore as embodiment wherein p represents    2;    or-   B-11) compounds of class B or, whenever possible, any subgroup    thereof as mentioned hereinbefore as embodiment wherein Z represents    C₁₋₆alkanediyl, in particular CH₂ or CH₂—CH₂;    or-   B-12) compounds of class B or, whenever possible, any subgroup    thereof as mentioned hereinbefore as embodiment wherein R^(x)    represents hydrogen;    or-   B-13) compounds of class B or, whenever possible, any subgroup    thereof as mentioned hereinbefore as embodiment wherein R⁸    represents hydrogen;    or-   B-14) compounds of class B or, whenever possible, any subgroup    thereof as mentioned hereinbefore as embodiment wherein R⁸    represents halo, C₁₋₄alkyl or C₁₋₄alkyl substituted with hydroxyl;    in particular R⁸ represents halo or C₁₋₄alkyl;    or-   B-15) compounds of class B or, whenever possible, any subgroup    thereof as mentioned hereinbefore as embodiment wherein R³    represents C₃₋₆cycloalkyl, phenyl, naphtalenyl, 1,3-benzodioxolyl or    a 6-membered aromatic heterocycle containing 1 or 2 N atoms, wherein    said C₃₋₆cyclo-alkyl, phenyl, naphtalenyl, 1,3-benzodioxolyl or    6-membered aromatic heterocycle may optionally be substituted with    at least one substituent, in particular one or two substituents,    preferably each substituent independently selected from hydroxyl;    carboxyl; halo; C₁₋₆alkyl optionally substituted with hydroxy;    polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy; C₁₋₆alkylthio;    C₁₋₆alkyloxycarbonyl; amino; mono- or di(C₁₋₄alkyl)amino;    C₁₋₄alkylcarbonylamino; Het; HetC₁₋₄alkyl;    or-   B-16) compounds of class B or any subgroup thereof as mentioned    hereinbefore as embodiment wherein one or more, preferably all, of    the following restrictions apply:-   a) X represents —NR^(x)—C(═O)—; or —Z—C(═O)—;-   b) the compound of class B is a compound of formula (I″), in    particular a compound of formula (I″) wherein R^(3a) and R^(3b)    represent halo; more in particular chloro; and wherein R^(3c)    represents hydrogen;-   c) A represents N;-   d) A represents CH;-   e) the dotted line does not represent a bond;-   f) Z represents C₁₋₆alkanediyl;-   g) R¹ represents a 5-membered monocyclic aromatic heterocycle    containing at least 2 heteroatoms, in particular pyrazolyl or    triazolyl; a 6-membered monocyclic aromatic heterocycle; or a    5-membered aromatic heterocycle containing at least 2 heteroatoms    fused with a 5-membered heterocycle; each of said heterocycles    optionally being substituted, in particular substituted with oxo,    C₁₋₆alkyl optionally substituted with aryl-C(═O)—; hydroxyC₁₋₆alkyl    optionally substituted with aryl; C₃₋₆cycloalkyl-NR^(x)—;    Het-NR^(x)—; arylC₁₋₄alkyl-NR^(x)—; aryl; arylC₁₋₄alkyl.-   h) R^(x) represents hydrogen;    or-   B-17) compounds of class B or any subgroup thereof as mentioned    hereinbefore as embodiment wherein one or more, preferably all, of    the following restrictions apply:-   a) A represents CH or N;-   b) the dotted line does not represents a bond in case A represents a    carbon atom;-   c) X represents —NR^(x)—C(═O)—; —Z—C(═O)—; —Z—NR^(x)—C(═O)—;-   d) Z represents a bivalent radical selected from C₁₋₆alkanediyl;-   e) R^(x) represents hydrogen;-   f) R¹ represents a 5-membered monocyclic heterocycle containing at    least 2 heteroatoms; a 6-membered aromatic monocyclic heterocycle;    or a 5-membered heterocycle containing at least 2 heteroatoms fused    with a 5-membered heterocycle; wherein each of said heterocycles    such as for example pyrazolyl, triazolyl, oxadiazolyl, pyrimidinyl,    imidazopyrazolyl or imidazothienyl, may optionally be substituted    with at least one substituent, in particular one or two    substituents, each substituent independently being selected from    oxo; C₁₋₆alkyl optionally substituted with C₁₋₄alkyloxycarbonyl;    hydroxyC₁₋₆alkyl optionally substituted with aryl; mono- or    di(C₁₋₆alkyl)amino; R⁵R⁴N—C₁₋₆alkyl; Het-NR^(x)—;    arylC₁₋₄alkyl-NR^(x)—; C₃₋₆cycloalkyl; C₃₋₆cycloalkylC₁₋₄alkyl;    aryl; arylC₁₋₄alkyl; aryl-C(═O)—C₁₋₄alkyl; Het;-   g) R³ represents C₃₋₆cycloalkyl, phenyl, naphtalenyl,    1,3-benzodioxolyl, or a 6-membered aromatic heterocycle containing 1    or 2 N atoms, wherein said C₃₋₆cyclo-alkyl, phenyl, naphtalenyl,    1,3-benzodioxolyl or 6-membered aromatic heterocycle may optionally    be substituted with at least one substituent, in particular one or    two substituents, each substituent independently selected from    hydroxyl; carboxyl; halo; C₁₋₆alkyl optionally substituted with    hydroxy; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy; C₁₋₆alkylthio; C₁₋₆    alkyloxycarbonyl; mono- or di(C₁₋₄alkyl)amino;    C₁₋₄alkyl-carbonylamino; Het; HetC₁₋₄alkyl;-   h) R⁴ represents hydrogen or C₁₋₄alkyl;-   i) R⁵ represents hydrogen or C₁₋₄alkyl;-   j) R⁸ represents hydrogen;-   k) aryl represents phenyl or phenyl substituted with at least one    substituent, in particular one substituent, said substituent being    selected from halo; C₁₋₆alkyl; C₁₋₆alkyloxy;-   l) Het represents a monocyclic non-aromatic or aromatic heterocycle    containing at least one heteroatom selected from O, S, S(═O)_(p) or    N; said monocyclic heterocycle optionally being substituted with    C₁₋₆alkyloxycarbonyl;    or-   B-18) compounds of class B selected from

A X R¹ R^(q) N

N

N

N

N

N

including any stereochemically isomeric form thereof;a N-oxide thereof, a pharmaceutically acceptable salt thereof or asolvate thereof.

The next embodiments of the present invention are those combinations ofa DGAT inhibitor, more in particular a DGAT1 inhibitor and a PPARagonist, in particular a PPAR-α agonist, more in particular a fibrate,even more in particular fenofibrate; wherein the DGAT inhibitor isselected from compounds of Class C. Preferred embodiments of compoundsof class C are:

-   C-1) compounds of class C having the following formula (I)

including any stereochemically isomeric form thereof, wherein

-   A represents CH or N;-   the dotted line represents an optional bond in case A represents a    carbon atom;-   X represents —NR^(x)—C(═O)—; —Z—C(═O)—; —Z—NR^(x)—C(═O)—; —C(═O)—Z—;    —NR^(x)—C(═O)—Z—; —C(═S)—; —NR^(x)—C(═S)—; —Z—C(═S)—;    —Z—NR^(x)—C(═S)—; —C(═S)—Z—; —NR^(x)—C(═S)—Z—;-   Z represents a bivalent radical selected from C₁₋₆alkanediyl,    C₂₋₆alkenediyl or C₂₋₆alkynediyl; wherein each of said    C₁₋₆alkanediyl, C₂₋₆alkenediyl or C₂₋₆alkynediyl may optionally be    substituted with hydroxyl;-   R^(x) represents hydrogen or C₁₋₄alkyl;-   Y represents —C(═O)—NR^(x)— or —NR^(x)—C(═O)—;-   R¹ represents C₃₋₆cycloalkyl; aryl¹ or Het¹;-   R² represents C₃₋₆cycloalkyl, phenyl, naphtalenyl,    2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl, wherein said    C₃₋₆cycloalkyl, phenyl, naphtalenyl, 2,3-dihydro-1,4-benzodioxinyl,    1,3-benzodioxolyl may optionally be substituted with at least one    substituent, in particular one, two, three, four or five    substituents, each substituent independently selected from hydroxyl;    carboxyl; halo; C₁₋₆alkyl optionally substituted with hydroxy;    polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted with    C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhalo-C₁₋₆alkyloxy;    C₁₋₆alkyloxycarbonyl wherein C₁₋₆alkyl may optionally be substituted    with aryl; cyano; C₁₋₆alkylcarbonyl; nitro; amino; mono- or    di(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl; R⁴R³N—C(═O)—;    R⁴R³N—C₁₋₆alkyl; C₃₋₆cycloalkyl; C₃₋₆cycloalkylC₁₋₄alkyl;    C₃₋₆cycloalkyl-C(═O)—; aryl; aryloxy; arylC₁₋₄alkyl; aryl-C(═O)—;    Het; HetC₁₋₄alkyl; Het-C(═O)—; Het-O—;-   R³ represents hydrogen; C₁₋₄alkyl optionally substituted with    hydroxyl or C₁₋₄alkyloxy; R⁶R⁵N—C₁₋₄alkyl; C₁₋₄alkyloxy; Het; aryl;    R⁶R⁵N—C(═O)—C₁₋₄alkyl;-   R⁴ represents hydrogen or C₁₋₄alkyl;-   R⁵ represents hydrogen; C₁₋₄alkyl; C₁₋₄alkylcarbonyl;-   R⁶ represents hydrogen or C₁₋₄alkyl; or-   R⁵ and R⁶ may be taken together with the nitrogen to which they are    attached to form a saturated monocyclic 5, 6 or 7-membered    heterocycle which may further contain one or more heteroatoms    selected from O, S, S(═O)_(p) or N; and which heterocycle may    optionally be substituted with C₁₋₄alkyl;-   aryl represents phenyl or phenyl substituted with at least one    substituent, in particular one, two, three, four or five    substituents, each substituent independently being selected from    hydroxyl; carboxyl; halo; C₁₋₆alkyl optionally substituted with    C₁₋₄alkyloxy, amino or mono- or di(C₁₋₄alkyl)amino;    polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted with    C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy;    C₁₋₆alkyloxycarbonyl; cyano; aminocarbonyl; mono- or    di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono-    or di(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl;-   aryl¹ represents phenyl, naphthalenyl or fluorenyl; each of said    phenyl, naphthalenyl or fluorenyl optionally substituted with at    least one substituent, in particular one, two, three, four or five    substituents, each substituent independently being selected from    hydroxyl; oxo; carboxyl; halo; C₁₋₆alkyl optionally substituted with    aryl-C(═O)—; hydroxyC₁₋₆alkyl optionally substituted with aryl or    aryl-C(═O)—; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted    with C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy;    C₁₋₆alkyloxy-carbonyl wherein C₁₋₆alkyl may optionally be    substituted with aryl; cyano; aminocarbonyl; mono- or    di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono-    or di(C₁₋₆alkyl)amino; C₃₋₆cycloalkyl-NR^(x)—; aryl-NR^(x)—;    Het-NR^(x)—; C₃₋₆cycloalkylC₁₋₄alkyl-NR^(x)—; arylC₁₋₄alkyl-NR^(x)—;    HetC₁₋₄alkyl-NR^(x)—; —S(═O)_(p)—C₁₋₄alkyl; C₃₋₆ cycloalkyl;    C₃₋₆cycloalkylC₁₋₄alkyl; C₃₋₆cycloalkyl-C(═O)—; aryl; aryloxy;    arylC₁₋₄alkyl; aryl-C(═O)—; Het; HetC₁₋₄alkyl; Het-C(═O)—; Het-O—;-   Het represents a monocyclic non-aromatic or aromatic heterocycle    containing at least one heteroatom selected from O, S, S(═O)_(p) or    N; or a bicyclic or tricyclic non-aromatic or aromatic heterocycle    containing at least one heteroatom selected from O, S, S(═O)_(p) or    N; said monocyclic heterocycle or said bi- or tricyclic heterocycle    optionally being substituted with at least one substituent, in    particular one, two, three, four or five substituents, each    substituent independently being selected from hydroxyl; oxo;    carboxyl; halo; C₁₋₆alkyl optionally substituted with C₁₋₄alkyloxy,    amino or mono- or di(C₁₋₄alkyl)amino; polyhaloC₁₋₆alkyl;    C₁₋₆alkyloxy optionally substituted with C₁₋₄alkyloxy;    C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy; C₁₋₆alkyl-oxycarbonyl; cyano;    aminocarbonyl; mono- or di(C₁₋₄alkyl)aminocarbonyl;    C₁₋₆alkylcarbonyl; nitro; amino; mono- or di(C₁₋₄alkyl)amino;    —S(═O)_(p)—C₁₋₄alkyl;-   Het¹ represents a monocyclic non-aromatic or aromatic heterocycle    containing at least one heteroatom selected from O, S, S(═O)_(p) or    N; or a bicyclic or tricyclic non-aromatic or aromatic heterocycle    containing at least one heteroatom selected from O, S, S(═O)_(p) or    N; said monocyclic heterocycle or said bi- or tricyclic heterocycle    optionally being substituted with at least one substituent, in    particular one, two, three, four or five substituents, each    substituent independently being selected from hydroxyl; oxo;    carboxyl; halo; C₁₋₆alkyl optionally substituted with aryl-C(═O)—;    hydroxyC₁₋₆alkyl optionally substituted with aryl or aryl-C(═O)—;    polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted with    C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy;    C₁₋₆alkyloxy-carbonyl wherein C₁₋₆alkyl may optionally be    substituted with aryl; cyano; aminocarbonyl; mono- or    di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono-    or di(C₁₋₆alkyl)amino; C₃₋₆cycloalkyl-NR^(x)—; aryl-NR^(x)—;    Het-NR^(x)—; C₃₋₆cycloalkylC₁₋₄alkyl-NR^(x)—; arylC₁₋₄alkyl-NR^(x)—;    HetC₁₋₄alkyl-NR^(x)—; —S(═O)_(p)—C₁₋₄alkyl; C₃₋₆cycloalkyl;    C₃₋₆cycloalkylC₁₋₄alkyl; C₃₋₆cycloalkyl-C(═O)—; aryl; aryloxy;    arylC₁₋₄alkyl; aryl-C(═O)—; Het; HetC₁₋₄alkyl; Het-C(═O)—; Het-O—;-   p represents 1 or 2;-   a N-oxide thereof, a pharmaceutically acceptable salt thereof or a    solvate thereof;    or-   C-2) compounds of class C or, whenever possible, any subgroup    thereof as mentioned hereinbefore as embodiment wherein X represents    —O—C(═O)—; —NR^(x)—C(═O)—; —Z—C(═O)—; —Z—NR^(x)—C(═O)—; —C(═O)—Z—;    —NR^(x)—C(═O)—Z—; —NR^(x)—C(═S)—; in particular wherein X represents    —NR^(x)—C(═O)—; —Z—C(═O)—; —Z—NR^(x)—C(═O)—; —C(═O)—Z—;    —NR^(x)—C(═O)—Z—; —NR^(x)—C(═S)—; more in particular wherein X    represents —NR^(x)—C(═O)—; —Z—C(═O)—; —Z—NR^(x)—C(═O)—; even more in    particular X represents —NR^(x)—C(═O)— or —Z—NR^(x)—C(═O)—; or X    represents —NR^(x)—C(═O)— or —Z—C(═O)—. Or X represents —O—C(═O)—;    —C(═O)—C(═O)—; —NR^(x)—C(═O)—; —Z—C(═O)—; —Z—NR^(x)—C(═O)—; —C(═S)—;    —NR^(x)—C(═S)—; —Z—C(═S)—; —Z—NR^(x)—C(═S)—;    or-   C-3) compounds of class C or, whenever possible, any subgroup    thereof as mentioned hereinbefore as embodiment wherein A represents    N;    or-   C-4) compounds of class C or, whenever possible, any subgroup    thereof as mentioned hereinbefore as embodiment wherein A represents    CH, in particular wherein A represents CH and the dotted line does    not represent a bond;    or-   C-5) compounds of class C or, whenever possible, any subgroup    thereof as mentioned hereinbefore as embodiment wherein R¹    represents aryl¹ or Het¹; in particular optionally substituted    phenyl, optionally substituted fluorenyl or an optionally    substituted monocyclic non-aromatic or aromatic heterocycle    containing at least one heteroatom each independently selected from    O, S, S(═O)_(p) or N, in particular S or N; more in particular    phenyl or fluorenyl, said phenyl or fluorenyl optionally substituted    with one or two substituents, said substituents independently    selected from oxo, carboxyl, halo, C₁₋₆alkyl optionally substituted    with carboxyl or C₁₋₄alkyloxycarbonyl, C₁₋₆alkyloxy,    C₁₋₆alkyloxycarbonyl, amino, aryl, Het or polyhaloC₁₋₆alkyl; or a    4-, 5- or 6-membered non-aromatic or aromatic heterocycle, such as    for example azetidinyl, thiazolidinyl, thiazolyl, pyrrolidinyl,    piperidinyl, said 5- or 6-membered heterocycle optionally    substituted with one or two substituents, said substituents    independently selected from hydroxyl, oxo, C₁₋₆alkyl,    C₁₋₆alkyloxycarbonyl, aryl or Het;    or-   C-6) compounds of class C or, whenever possible, any subgroup    thereof as mentioned hereinbefore as embodiment wherein R²    represents C₃₋₆cycloalkyl, phenyl, 2,3-dihydro-1,4-benzodioxinyl or    a 6-membered aromatic heterocycle containing 1 or 2 N atoms such as    for example pyridyl, wherein said phenyl or heterocycle are    optionally substituted with one to four substituents, preferably    each substituent independently selected from halo, C₁₋₆alkyl,    C₁₋₆alkyloxy, C₁₋₆alkylthio, C₁₋₆alkyloxycarbonyl, nitro, amino,    mono- or di(C₁₋₄alkyl)amino, aryloxy, R⁴R³N—C₁₋₆alkyl,    Het-C(═O)—C₁₋₄alkyl;    or-   C-7) compounds of class C or, whenever possible, any subgroup    thereof as mentioned hereinbefore as embodiment wherein the compound    of class C is a compound of formula (I′)

wherein R^(3a) and R^(3b) each independently represent hydrogen;hydroxyl; carboxyl; halo; C₁₋₆alkyl; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxyoptionally substituted with C₁₋₄alkyloxy; C₁₋₆alkylthio;polyhaloC₁₋₆alkyloxy; C₁₋₆alkyloxycarbonyl; cyano; aminocarbonyl; mono-or di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono- ordi(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl; and wherein R^(3c) representshydrogen; hydroxyl; carboxyl; halo; C₁₋₆alkyl; polyhaloC₁₋₆alkyl;C₁₋₆alkyloxy optionally substituted with C₁₋₄alkyloxy; C₁₋₆alkylthio;polyhalo-C₁₋₆alkyloxy; C₁₋₆alkyloxycarbonyl wherein C₁₋₆alkyl mayoptionally be substituted with aryl; cyano; C₁₋₆alkylcarbonyl; nitro;amino; mono- or di(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl; R⁴R³N—C(═O)—;R⁴R³N—C₁₋₆alkyl; C₃₋₆cycloalkyl; aryl; aryloxy; arylC₁₋₄alkyl;aryl-C(═O)—C₁₋₄alkyl; aryl-C(═O)—; Het; HetC₁₋₄alkyl;Het-C(═O)—C₁₋₄alkyl; Het-C(═O)—; Het-O—;or

-   C-8) compounds of class C or, whenever possible, any subgroup    thereof as mentioned hereinbefore as embodiment wherein the compound    of class C is a compound of formula (I″)

wherein R^(3a) and R^(3b) each independently represent hydrogen;hydroxyl; carboxyl; halo; C₁₋₆alkyl; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxyoptionally substituted with C₁₋₄alkyloxy; C₁₋₆alkylthio;polyhaloC₁₋₆alkyloxy; C₁₋₆alkyloxycarbonyl; cyano; aminocarbonyl; mono-or di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono- ordi(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl; and wherein R^(3c) representshydrogen; hydroxyl; carboxyl; halo; C₁₋₆alkyl; polyhaloC₁₋₆alkyl;C₁₋₆alkyloxy optionally substituted with C₁₋₄alkyloxy; C₁₋₆alkylthio;polyhalo-C₁₋₆alkyloxy; C₁₋₆alkyloxycarbonyl wherein C₁₋₆alkyl mayoptionally be substituted with aryl; cyano; C₁₋₆alkylcarbonyl; nitro;amino; mono- or di(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl; R⁴R³N—C(═O)—;R⁴R³N—C₁₋₆alkyl; C₃₋₆cycloalkyl; aryl; aryloxy; arylC₁₋₄alkyl;aryl-C(═O)—C₁₋₄alkyl; aryl-C(═O)—; Het; HetC₁₋₄alkyl;Het-C(═O)—C₁₋₄alkyl; Het-C(═O)—; Het-O—;or

-   C-9) compounds of class C or any subgroup thereof as mentioned    hereinbefore as embodiment wherein the compound of formula (I) is a    compound of formula (I′) or (I″) and wherein R^(3a) and R^(3b) each    independently represent halo, C₁₋₆alkyl or C₁₋₆alkyloxy; in    particular halo or C₁₋₆alkyl; more in particular both R^(3a) and    R^(3b) represent halo, more in particular both R^(3a) and R^(3b)    represent chloro;    or-   C-10) compounds of class C or, whenever possible, any subgroup    thereof as mentioned hereinbefore as embodiment wherein the compound    of formula (I) is a compound of formula (I′) or (I″) and wherein    R^(3c) represents amino; mono- or di(C₁₋₄alkyl)amino; R⁴R³N—C(═O)—;    R⁴R³N—C₁₋₆alkyl; Het-C(═O)— or HetC₁₋₄alkyl; or R^(3c) represents    hydrogen;    or-   C-11) compounds of class C or, whenever possible, any subgroup    thereof as mentioned hereinbefore as embodiment wherein p represents    2;    or-   C-12) compounds of class C or, whenever possible, any subgroup    thereof as mentioned hereinbefore as embodiment wherein Z represents    C₁₋₆alkanediyl or C₂₋₆alkenediyl, in particular C₁₋₆alkanediyl, more    in particular —CH₂—;    or-   C-13) compounds of class C or, whenever possible, any subgroup    thereof as mentioned hereinbefore as embodiment wherein R^(x)    represents hydrogen;    or-   C-14) compounds of class C or, whenever possible, any subgroup    thereof as mentioned hereinbefore as embodiment wherein Y represents    —NR^(x)—C(═O)—;    or-   C-15) compounds of class C or, whenever possible, any subgroup    thereof as mentioned hereinbefore as embodiment wherein Y represents    —C(═O)—NR^(x)—;    or-   C-16) compounds of class C or, whenever possible, any subgroup    thereof as mentioned hereinbefore as embodiment wherein R⁷    represents hydrogen;    or-   C-17) compounds of class C or, whenever possible, any subgroup    thereof as mentioned hereinbefore as embodiment wherein R⁷    represents halo, C₁₋₄alkyl or C₁₋₄alkyl substituted with hydroxyl;    in particular halo;    or-   C-18) compounds of class C or, whenever possible, any subgroup    thereof as mentioned hereinbefore as embodiment wherein aryl    represents phenyl or phenyl substituted with halo, C₁₋₆alkyl,    polyhaloC₁₋₆alkyl or C₁₋₆alkyloxycarbonyl;    or-   C-19) compounds of class C or, whenever possible, any subgroup    thereof as mentioned hereinbefore as embodiment wherein Het    represents a monocyclic non-aromatic or aromatic heterocycle    containing at least one heteroatom each independently selected from    O, S, S(═O)_(p) or N; or a bicyclic non-aromatic or aromatic    heterocycle containing at least one heteroatom each independently    selected from O, S, S(═O)_(p) or N, in particular N; said monocyclic    heterocycle or said bicyclic heterocycle optionally being    substituted with one or two substituents, each substituent    independently being selected from oxo; or C₁₋₆alkyl;    or-   C-20) compounds of class C or, whenever possible, any subgroup    thereof as mentioned hereinbefore as embodiment wherein one or more,    preferably all, of the following restrictions apply:-   a) X represents —NR^(x)—C(═O)—; —Z—NR^(x)—C(═O)—; or —NR^(x)—C(═S)—;-   b) R¹ represents aryl¹ or Het¹;-   c) R² represents C₃₋₆cycloalkyl, phenyl or    2,3-dihydro-1,4-benzodioxinyl, wherein said phenyl is optionally    substituted with one to four substituents, each substituent    independently selected from halo, C₁₋₆alkyl, C₁₋₆alkyloxy,    C₁₋₆alkylthio, C₁₋₆alkyloxycarbonyl, nitro, amino, mono- or    di(C₁₋₄alkyl)amino, aryloxy;-   d) A represents N;-   e) A represents CH;-   f) Z represents C₁₋₆alkanediyl or C₂₋₆alkenediyl;-   g) R^(x) represents hydrogen.-   h) aryl¹ represents phenyl or fluorenyl, said phenyl or fluorenyl    optionally substituted with halo, C₁₋₆alkyl or polyhaloC₁₋₆alkyl;-   i) Het¹ represents a 4-, 5- or 6-membered non-aromatic or aromatic    heterocycle, such as for example azetidinyl, thiazolidinyl,    thiazolyl, pyrrolidinyl, piperidinyl, said 5- or 6-membered    heterocycle optionally substituted with hydroxyl, oxo, C₁₋₆alkyl,    C₁₋₆alkyloxycarbonyl, aryl or Het;-   j) Y represents —NR^(x)—C(═O)—;-   k) R⁷ represents hydrogen;    or-   C-21) compounds of class C or, whenever possible, any subgroup    thereof as mentioned hereinbefore as embodiment wherein one or more,    preferably all, of the following restrictions apply:-   a) A represents CH;-   b) A represents N;-   c) the dotted line represents a bond in case A represents a carbon    atom;-   d) the dotted line doesn't represents a bond in case A represents a    carbon atom;-   e) X represents —O—C(═O)—; —NR^(x)—C(═O)—; —Z—C(═O)—;    —Z—NR^(x)—C(═O)—; —NR^(x)—C(═S)—;-   f) Z represents C₁₋₆alkanediyl;-   g) R^(x) represents hydrogen;-   h) Y represents —C(═O)—NR^(x)— or —NR^(x)—C(═O)—;-   i) R¹ represents aryl¹ or Het¹;-   j) R² represents C₃₋₆cycloalkyl, phenyl,    2,3-dihydro-1,4-benzodioxinyl, or a 6-membered aromatic heterocycle    containing 1 or 2 N atoms, wherein said C₃₋₆cycloalkyl, phenyl,    2,3-dihydro-1,4-benzodioxinyl, or 6-membered aromatic heterocycle    containing 1 or 2 N atoms may optionally be substituted with at    least one substituent, in particular one to four substituents, each    substituent independently selected from halo; C₁₋₆alkyl;    C₁₋₆alkyloxy; C₁₋₆alkylthio; C₁₋₆alkyloxycarbonyl; nitro; mono- or    di(C₁₋₄alkyl)amino; R⁴R³N—C₁₋₆alkyl; aryloxy; Het-C(═O)—C₁₋₄alkyl;-   k) R³ represents C₁₋₄alkyl;-   l) R⁴ represents C₁₋₄alkyl;-   m) R⁷ represents hydrogen or halo;-   n) aryl represents phenyl or phenyl substituted with halo;    C₁₋₆alkyl; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxycarbonyl;-   o) aryl¹ represents phenyl or fluorenyl; each of said phenyl or    fluorenyl optionally substituted with one or two substituents, each    substituent independently being selected from oxo; carboxyl; halo;    C₁₋₆alkyl optionally substituted with carboxyl or    C₁₋₄alkyloxycarbonyl; C₁₋₆alkyloxy; C₁₋₆alkyloxy-carbonyl; amino;    aryl; Het;-   p) Het represents a monocyclic non-aromatic or aromatic heterocycle    containing at least one heteroatom each independently selected from    O, S, S(═O)_(p) or N; or a bicyclic non-aromatic or aromatic    heterocycle containing at least one heteroatom each independently    selected from N; said monocyclic heterocycle or said bicyclic    heterocycle optionally being substituted with one or two    substituents, each substituent independently being selected from oxo    or C₁₋₆alkyl;-   q) Het¹ represents a monocyclic non-aromatic or aromatic heterocycle    containing at least one heteroatom each independently selected from    S or N; said monocyclic heterocycle optionally being substituted    with at least one substituent, in particular one or two    substituents, each substituent independently being selected from    hydroxyl; oxo; C₁₋₆alkyl; C₁₋₆alkyloxy-carbonyl; aryl; Het;-   r) p represents 2;    or-   C-22)compounds of class C selected from

including any stereochemically isomeric form thereof;

-   a N-oxide thereof, a pharmaceutically acceptable salt thereof or a    solvate thereof;    or-   C-23) compounds of formula (I), wherein the compound is selected    from-   4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide    (compound 151 Class C);-   4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]hydroxyacetyl]-1-piperazinyl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide    (compound 152 Class C);-   4-[4-[[2,6-dichloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide    (compound 147 Class C);-   4-[4-[[2,6-dichloro-4-[[4-(methylsulfonyl)-1-piperazinyl]methyl]phenyl]acetyl]-1-piperazinyl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide    (compound 150 Class C);-   4-[4-[[4-[(4-acetyl-1-piperazinyl)methyl]-2,6-dichlorophenyl]acetyl]-1-piperazinyl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide    (compound 149 Class C);-   4-[4-[[2,6-dichloro-4-[(4-ethyl-1-piperazinyl)methyl]phenyl]acetyl]-1-piperazinyl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide    (compound 148 Class C);-   including any stereochemically isomeric form thereof;-   a N-oxide thereof, a pharmaceutically acceptable salt thereof or a    solvate thereof;    or-   C-24) compounds of class C or, whenever possible, any subgroup    thereof as mentioned hereinbefore as embodiment wherein R²    represents hydrogen, C₁₋₆alkyl or C₂₋₆alkenyl.

The next embodiments of the present invention are those combinations ofa DGAT inhibitor, more in particular a DGAT1 inhibitor and a PPARagonist, in particular a PPAR-α agonist, more in particular a fibrate,even more in particular fenofibrate; wherein the DGAT inhibitor isselected from compounds of Class D. Preferred embodiments of compoundsof class D are:

-   D-1) compounds of class D having the following formula (I)

including any stereochemically isomeric form thereof, wherein

-   A represents CH or N;-   the dotted line represents an optional bond in case A represents a    carbon atom;-   X represents —C(═O)—; —NR^(x)—C(═O)—; —Z¹—C(═O)—; —Z¹—NR^(x)—C(═O)—;    —C(═O)—Z¹—; —NR^(x)—C(═O)—Z¹—; —S(═O)_(p)—; —C(═S)—; —NR^(x)—C(═S)—;    —Z¹—C(═S)—; —Z¹—NR^(x)—C(═S)—; —C(═S)—Z¹—; —NR^(x)—C(═S)—Z¹—;-   Z¹ represents a bivalent radical selected from C₁₋₆alkanediyl,    C₂₋₆alkenediyl or C₂₋₆alkynediyl; wherein each of said    C₁₋₆alkanediyl, C₂₋₆alkenediyl or C₂₋₆alkynediyl may optionally be    substituted with hydroxyl;-   Y represents NR^(x)—C(═O)—Z²—; —NR^(x)—C(═O)—Z²—NR^(y)—;    —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—; —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—O—;    —NR^(x)—C(═O)—Z²—O—; —NR^(x)—C(═O)—Z²—O—C(═O)—;    —NR^(x)—C(═O)—Z²—C(═O)—; —NR^(x)—C(═O)—Z²—C(═O)—O—;    —NR^(x)—C(═O)—O—Z²—C(═O)—; —NR^(x)—C(═O)—O—Z²—C(═O)—O—;    —NR^(x)—C(═O)—O—Z²—O—C(═O)—; —NR^(x)—C(═O)—Z²—C(═O)—NR^(y)—;    —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—NR^(y)—; —C(═O)—Z²—; —C(═O)—Z²—O—;    —C(═O)—NR^(x)—Z²—; —C(═O)—NR^(x)—Z²—O—; —C(═O)—NR^(x)—Z²—C(═O)—O—;    —C(═O)—NR^(x)—Z²—O—C(═O)—; —C(═O)—NR^(x)—O—Z²—;    —C(═O)—NR^(x)—Z²—NR^(y)—; —C(═O)—NR^(x)—Z²—NR^(y)—C(═O)—;    —C(═O)—NR^(x)—Z²—NR^(y)—C(═O)—O—;-   Z² represents a bivalent radical selected from C₁₋₆alkanediyl,    C₂₋₆alkenediyl or C₂₋₆alkynediyl; wherein each of said    C₁₋₆alkanediyl, C₂₋₆alkenediyl or C₂₋₆alkynediyl may optionally be    substituted with C₁₋₄alkyloxy, C₁₋₄alkylthio, hydroxyl, cyano or    aryl; and wherein two hydrogen atoms attached to the same carbon    atom in the definition of Z² may optionally be replaced by    C₁₋₆alkanediyl;-   R^(x) represents hydrogen or C₁₋₄alkyl;-   R^(y) represents hydrogen; C₁₋₄alkyl optionally substituted with    C₃₋₆cycloalkyl or aryl or Het; C₂₋₄alkenyl; or —S(═O)_(p)-aryl;-   R¹ represents C₁₋₁₂alkyl optionally substituted with cyano,    C₁₋₄alkyloxy, C₁₋₄alkyl-oxyC₁₋₄alkyloxy, C₃₋₆cycloalkyl or aryl;    C₂₋₆alkenyl; C₂₋₆alkynyl; C₃₋₆cycloalkyl; aryl¹; aryl¹C₁₋₆alkyl;    Het¹; or Het¹C₁₋₆alkyl; provided that when Y represents    —NR^(x)—C(═O)—Z²—; —NR^(x)—C(═O)—Z²—NR^(y);    —NR^(x)—C(═O)—Z²—C(═O)—NR^(y)—; —C(═O)—Z²—;    —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—NR^(y)—; —C(═O)—NR^(x)—Z²—;    —C(═O)—NR^(x)—O—Z²—; or —C(═O)—NR^(x)—Z²—NR^(y)—; then R¹ may also    represent hydrogen;-   R² represents hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl or R³;-   R³ represents C₃₋₆cycloalkyl, phenyl, naphtalenyl,    2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl, wherein said    C₃₋₆cycloalkyl, phenyl, naphtalenyl, 2,3-dihydro-1,4-benzodioxinyl,    1,3-benzodioxolyl may optionally be substituted with at least one    substituent, in particular one, two, three, four or five    substituents, each substituent independently selected from hydroxyl;    carboxyl; halo; C₁₋₆alkyl optionally substituted with hydroxy;    polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted with    C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhalo-C₁₋₆alkyloxy;    C₁₋₆alkyloxycarbonyl wherein C₁₋₆alkyl may optionally be substituted    with aryl; cyano; C₁₋₆alkylcarbonyl; nitro; amino; mono- or    di(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl; R⁵R⁴N—C(═O)—;    R⁵R⁴N—C₁₋₆alkyl; C₃₋₆cycloalkyl; C₃₋₆cycloalkylC₁₋₄alkyl;    C₃₋₆cycloalkyl-C(═O)—; aryl; aryloxy; arylC₁₋₄alkyl; aryl-C(═O)—;    Het; HetC₁₋₄alkyl; Het-C(═O)—; Het-O—;-   R⁴ represents hydrogen; C₁₋₄alkyl optionally substituted with    hydroxyl or C₁₋₄alkyloxy; R⁷R⁶N—C₁₋₄alkyl; C₁₋₄alkyloxy; Het; aryl;    R⁷R⁶N—C(═O)—C₁₋₄alkyl;-   R⁵ represents hydrogen or C₁₋₄alkyl;-   R⁶ represents hydrogen; C₁₋₄alkyl; C₁₋₄alkylcarbonyl;-   R⁷ represents hydrogen or C₁₋₄alkyl; or-   R⁶ and R⁷ may be taken together with the nitrogen to which they are    attached to form a saturated monocyclic 5, 6 or 7-membered    heterocycle which may further contain one or more heteroatoms    selected from O, S, S(═O)_(p) or N; and which heterocycle may    optionally be substituted with C₁₋₄alkyl;-   aryl represents phenyl or phenyl substituted with at least one    substituent, in particular one, two, three, four or five    substituents, each substituent independently being selected from    hydroxyl; carboxyl; halo; C₁₋₆alkyl optionally substituted with    C₁₋₄alkyloxy, amino or mono- or di(C₁₋₄alkyl)amino;    polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted with    C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy;    C₁₋₆alkyloxycarbonyl; cyano; aminocarbonyl; mono- or    di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono-    or di(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl;-   aryl¹ represents phenyl, naphthalenyl or fluorenyl; each of said    phenyl, naphthalenyl or fluorenyl optionally substituted with at    least one substituent, in particular one, two, three, four or five    substituents, each substituent independently being selected from    hydroxyl; oxo; carboxyl; halo; C₁₋₆alkyl optionally substituted with    aryl-C(═O)—; hydroxyC₁₋₆alkyl optionally substituted with aryl or    aryl-C(═O)—; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted    with C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy;    C₁₋₆alkyloxy-carbonyl wherein C₁₋₆alkyl may optionally be    substituted with aryl; cyano; aminocarbonyl; mono- or    di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono-    or di(C₁₋₆alkyl)amino; C₃₋₆cycloalkyl-NR^(x)—; aryl-NR^(x)—;    Het-NR^(x)—; C₃₋₆cycloalkylC₁₋₄alkyl-NR^(x)—; arylC₁₋₄alkyl-NR^(x)—;    HetC₁₋₄alkyl-NR^(x)—; —S(═O)_(p)—C₁₋₄alkyl; C₃₋₆cycloalkyl;    C₃₋₆cycloalkylC₁₋₄alkyl; C₃₋₆cycloalkyl-C(═O)—; aryl; aryloxy;    arylC₁₋₄alkyl; aryl-C(═O)—; Het; HetC₁₋₄alkyl; Het-C(═O)—; Het-O—;-   Het represents a monocyclic non-aromatic or aromatic heterocycle    containing at least one heteroatom selected from O, S, S(═O)_(p) or    N; or a bicyclic or tricyclic non-aromatic or aromatic heterocycle    containing at least one heteroatom selected from O, S, S(═O)_(p) or    N; said monocyclic heterocycle or said bi- or tricyclic heterocycle    optionally being substituted with at least one substituent, in    particular one, two, three, four or five substituents, each    substituent independently being selected from hydroxyl; oxo;    carboxyl; halo; C₁₋₆alkyl optionally substituted with C₁₋₄alkyloxy,    amino or mono- or di(C₁₋₄alkyl)amino; polyhaloC₁₋₆alkyl;    C₁₋₆alkyloxy optionally substituted with C₁₋₄alkyloxy;    C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy; C₁₋₆alkyl-oxycarbonyl; cyano;    aminocarbonyl; mono- or di(C₁₋₄alkyl)aminocarbonyl;    C₁₋₆alkylcarbonyl; nitro; amino; mono- or di(C₁₋₄alkyl)amino;    —S(═O)_(p)—C₁₋₄alkyl;-   Het¹ represents a monocyclic non-aromatic or aromatic heterocycle    containing at least one heteroatom selected from O, S, S(═O)_(p) or    N; or a bicyclic or tricyclic non-aromatic or aromatic heterocycle    containing at least one heteroatom selected from O, S, S(═O)_(p) or    N; said monocyclic heterocycle or said bi- or tricyclic heterocycle    optionally being substituted with at least one substituent, in    particular one, two, three, four or five substituents, each    substituent independently being selected from hydroxyl; oxo;    carboxyl; halo; C₁₋₆alkyl optionally substituted with aryl-C(═O)—;    hydroxyC₁₋₆alkyl optionally substituted with aryl or aryl-C(═O)—;    polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted with    C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy;    C₁₋₆alkyloxy-carbonyl wherein C₁₋₆alkyl may optionally be    substituted with aryl; cyano; aminocarbonyl; mono- or    di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono-    or di(C₁₋₆alkyl)amino; C₃₋₆cycloalkyl-NR^(x)—; aryl-NR^(x)—;    Het-NR^(x)—; C₃₋₆cycloalkylC₁₋₄alkyl-NR^(x)—; arylC₁₋₄alkyl-NR^(x)—;    HetC₁₋₄alkyl-NR^(x)—; —S(═O)_(p)—C₁₋₄alkyl; C₃₋₆cycloalkyl;    C₃₋₆cycloalkylC₁₋₄alkyl; C₃₋₆cycloalkyl-C(═O)—; aryl; aryloxy;    arylC₁₋₄alkyl; aryl-C(═O)—; Het; HetC₁₋₄alkyl; Het-C(═O)—; Het-O—;-   p represents 1 or 2;-   a N-oxide thereof, a pharmaceutically acceptable salt thereof or a    solvate thereof;    or-   D-2) compounds of class D or any subgroup thereof as mentioned    hereinbefore as embodiment wherein X represents —C(═O)—C(═O)—;    —O—C(═O)—; —NR^(x)—C(═O)—; —Z¹—C(═O)—; —Z¹—NR^(x)—C(═O)—;    —C(═O)—Z¹—; —NR^(x)—C(═O)—Z¹—; —S(═O)_(p)—; —NR^(x)—C(═S)—; in    particular X represents —NR^(x)—C(═O)—; —Z¹—C(═O)—;    —Z¹—NR^(x)—C(═O)—; —C(═O)—Z¹—; —NR^(x)—C(═O)—Z¹—; —S(═O)_(p)—;    —NR^(x)—C(═S)—; more in particular X represents —NR^(x)—C(═O)—;    —Z¹—C(═O)—; —C(═O)—Z¹—; —Z¹—NR^(x)—C(═O)—; —NR^(x)—C(═S)— or    —S(═O)_(p)—; even more in particular X represents —NR^(x)—C(═O)— or    —Z¹—NR^(x)—C(═O)—; even more in particular —NR^(x)—C(═O)—;    or-   D-3) compounds of class D or any subgroup thereof as mentioned    hereinbefore as embodiment wherein A represents N;    or-   D-4) compounds of class D or any subgroup thereof as mentioned    hereinbefore as embodiment wherein A represents CH, in particular    wherein A represents CH and the dotted line does not represent a    bond;    or-   D-5) compounds of class D or any subgroup thereof as mentioned    hereinbefore as embodiment wherein R¹ represents C₃₋₆cycloalkyl;    adamantanyl; aryl¹; aryl¹C₁₋₆alkyl; Het¹; or Het¹C₁₋₆alkyl; aryl¹;    in particular aryl¹C₁₋₆alkyl; Het¹; or Het¹C₁₋₆alkyl; more in    particular aryl¹; aryl¹C₁₋₆alkyl; Het¹; or Het¹C₁₋₆alkyl, wherein    said aryl¹ or Het¹ represent phenyl, naphthalenyl, morpholinyl,    piperidinyl, piperazinyl, pyrrolidinyl, furanyl, imidazolyl,    thienyl, pyridyl; each of said cycles representing aryl¹ or Het¹    being optionally substituted with one or two substituents; in    particular with aryl, C₁₋₆alkyl, arylC₁₋₄alkyl, hydroxyl, halo,    polyhaloC₁₋₆alkyl, C₁₋₆alkyloxy, nitro, C₁₋₆alkyloxycarbonyl,    —S(═O)₂—C₁₋₄alkyl; more in particular with aryl, C₁₋₆alkyl,    arylC₁₋₄alkyl, halo, C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl,    —S(═O)₂—C₁₋₄alkyl. More in particular R¹ represents aryl¹ wherein    aryl¹ represents preferably optionally substituted phenyl. Even more    in particular R¹ represents phenyl substituted with C₁₋₆alkyloxy,    e.g. methoxy;    or-   D-6) compounds of class D or any subgroup thereof as mentioned    hereinbefore as embodiment wherein R¹ represents C₁₋₁₂alkyl    optionally substituted with cyano, C₁₋₄alkyloxy,    C₁₋₄alkyl-oxyC₁₋₄alkyloxy, C₃₋₆cycloalkyl or aryl; C₂₋₆alkenyl;    C₂₋₆alkynyl; provided that when Y represents —NR^(x)— C(═O)—Z²—;    —NR^(x)—C(═O)—Z²—NR^(y); —NR^(x)—C(═O)—Z²—C(═O)—NR^(y)—; —C(═O)—Z²—;    —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—NR^(y)—; —C(═O)—NR^(x)—Z²—;    —C(═O)—NR^(x)—O—Z²—; or —C(═O)—NR^(x)—Z²—NR^(y)—; then R¹ may also    represent hydrogen;    or-   D-7) compounds of class D or any subgroup thereof as mentioned    hereinbefore as embodiment wherein R² represents C₁₋₁₂alkyl; in    particular C₁₋₆alkyl;    or-   D-8) compounds of class D or any subgroup thereof as mentioned    hereinbefore as embodiment wherein R² represents C₁₋₆alkyl or R³; in    particular wherein R² represents R³ and said R³ represents phenyl,    naphthalenyl, 2,3-dihydrobenzofuranyl or 6-membered aromatic    heterocycle containing 1 or 2 N atoms, each of said cycles, in    particular phenyl, being optionally substituted with one to five    substituents, said substituents being in particular halo, C₁₋₆alkyl    optionally substituted with hydroxy, polyhaloC₁₋₆alkyl,    C₁₋₆alkylthio, polyhaloC₁₋₆alkyloxy, carboxyl, hydroxyl,    C₁₋₆alkylcarbonyl, C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl, nitro,    R⁵R⁴N—C(═O)—, R⁵R⁴N—C₁₋₆alkyl, HetC₁₋₄alkyl, Het-C(═O)—C₁₋₄alkyl,    Het-C(═O)—; said substituents being more in particular halo,    C₁₋₆alkyl optionally substituted with hydroxy, polyhaloC₁₋₆alkyl,    polyhaloC₁₋₆alkyloxy, carboxyl, hydroxyl, C₁₋₆alkylcarbonyl,    C₁₋₆alkyloxy, C₁₋₆alkylthio, C₁₋₆alkyloxycarbonyl, nitro,    R⁵R⁴N—C₁₋₆alkyl, HetC₁₋₄alkyl; more in particular wherein R²    represents phenyl substituted with one, two or three substituents,    preferably three substituents, each substituent being selected from    halo, e.g. chloro, or HetC₁₋₄alkyl, e.g. pyrrolidinylmethyl;    or-   D-9) compounds of class D or any subgroup thereof as mentioned    hereinbefore as embodiment wherein the compound of class D is a    compound of formula (I′)

wherein R^(3a) and R^(3b) each independently represent hydrogen;hydroxyl; carboxyl; halo; C₁₋₆alkyl; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxyoptionally substituted with C₁₋₄alkyloxy; C₁₋₆alkylthio;polyhaloC₁₋₆alkyloxy; C₁₋₆alkyloxycarbonyl; cyano; aminocarbonyl; mono-or di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono- ordi(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl; and wherein R^(3c) representshydrogen; hydroxyl; carboxyl; halo; C₁₋₆alkyl; polyhaloC₁₋₆alkyl;C₁₋₆alkyloxy optionally substituted with C₁₋₄alkyloxy; C₁₋₆alkylthio;polyhalo-C₁₋₆alkyloxy; C₁₋₆alkyloxycarbonyl wherein C₁₋₆alkyl mayoptionally be substituted with aryl; cyano; C₁₋₆alkylcarbonyl; nitro;amino; mono- or di(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl; R⁵R⁴N—C(═O)—;R⁵R⁴N—C₁₋₆alkyl; C₃₋₆cycloalkyl; aryl; aryloxy; arylC₁₋₄alkyl;aryl-C(═O)—C₁₋₄alkyl; aryl-C(═O)—; Het; HetC₁₋₄alkyl;Het-C(═O)—C₁₋₄alkyl; Het-C(═O)—; Het-O—;or

-   D-10) compounds of class D or any subgroup thereof as mentioned    hereinbefore as embodiment wherein the compound of class D is a    compound of formula (I″)

wherein R^(3a) and R^(3b) each independently represent hydrogen;hydroxyl; carboxyl; halo; C₁₋₆alkyl; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxyoptionally substituted with C₁₋₄alkyloxy; C₁₋₆alkylthio;polyhaloC₁₋₆alkyloxy; C₁₋₆alkyloxycarbonyl; cyano; aminocarbonyl; mono-or di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono- ordi(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl; and wherein R^(3c) representshydrogen; hydroxyl; carboxyl; halo; C₁₋₆alkyl; polyhaloC₁₋₆alkyl;C₁₋₆alkyloxy optionally substituted with C₁₋₄alkyloxy; C₁₋₆alkylthio;polyhalo-C₁₋₆alkyloxy; C₁₋₆alkyloxycarbonyl wherein C₁₋₆alkyl mayoptionally be substituted with aryl; cyano; C₁₋₆alkylcarbonyl; nitro;amino; mono- or di(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl; R⁵R⁴N—C(═O)—;R⁵R⁴N—C₁₋₆alkyl; C₃₋₆cycloalkyl; aryl; aryloxy; aryl-C(═O)—C₁₋₄alkyl;arylC₁₋₄alkyl; aryl-C(═O)—; Het; HetC₁₋₄alkyl; Het-C(═O)—C₁₋₄alkyl;Het-C(═O)—; Het-O—;or

-   D-11) compounds of class D or any subgroup thereof as mentioned    hereinbefore as embodiment wherein the compound of class D is a    compound of formula (I′) or (I″) and wherein R^(3a) and R^(3b) each    independently represent halo, C₁₋₆alkyl or C₁₋₆alkyloxy; in    particular halo or C₁₋₆alkyl; more in particular both R^(3a) and    R^(3b) represent halo, more in particular both R^(3a) and R^(3b)    represent chloro;    or-   D-12) compounds of class D or any subgroup thereof as mentioned    hereinbefore as embodiment wherein the compound of formula (I) is a    compound of formula (I′) or (I″) and wherein R^(3c) represents    amino; mono- or di(C₁₋₄alkyl)amino; R⁵R⁴N—C(═O)—; R⁵R⁴N—C₁₋₆alkyl;    Het-C(═O)—; Het-C(═O)—C₁₋₄alkyl or HetC₁₋₄alkyl; or R^(3c)    represents hydrogen; more in particular wherein R^(3c) represents    amino; mono- or di(C₁₋₄alkyl)amino; R⁵R⁴N—C(═O)—; R⁵R⁴N—C₁₋₆alkyl;    Het-C(═O)— or HetC₁₋₄alkyl; or R^(3c) represents hydrogen; even more    in particular wherein R^(3c) represents HetC₁₋₄alkyl, e.g.    pyrrolidinylmethyl;    or-   D-13) compounds of class D or any subgroup thereof as mentioned    hereinbefore as embodiment wherein p represents 2;    or-   D-14) compounds of class D or any subgroup thereof as mentioned    hereinbefore as embodiment wherein Y represents —NR^(x)—C(═O)—Z²—;    —NR^(x)—C(═O)—Z²—NR^(y); —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—O—;    —NR^(x)—C(═O)—Z²—O—C(═O)—; —NR^(x)—C(═O)—Z²—C(═O)—O—;    —NR^(x)—C(═O)—O—Z²—C(═O)—O—; —NR^(x)—C(═O)—O—Z²—O—C(═O)—;    —NR^(x)—C(═O)—Z²—C(═O)—NR^(y)—;    —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—NR^(y)—; —C(═O)—NR^(x)—Z²—;    —C(═O)—NR^(x)—Z²—O—; —C(═O)—NR^(x)—Z²—C(═O)—O—;    —C(═O)—NR^(x)—Z²—O—C(═O)—; —C(═O)—NR^(x)—O—Z²—;    —C(═O)—NR^(x)—Z²—NR^(y)—; —C(═O)—NR^(x)—Z²—NR^(y)—C(═O)—;    —C(═O)—NR^(x)—Z²—NR^(y)—C(═O)—O—; or wherein Y represents    NR^(x)—C(═O)—Z²—; —NR^(x)—C(═O)—Z²—NR^(y);    —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—; —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—O—;    —NR^(x)—C(═O)—Z²—O—; —NR^(x)—C(═O)—Z²—C(═O)—O—;    —NR^(x)—C(═O)—Z²—C(═O)—NR^(y)—;    —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—NR^(y)—; —C(═O)—Z²—; or wherein Y    represents NR^(x)—C(═O)—Z²— or —NR^(x)—C(═O)—Z²—NR^(y); or wherein Y    represents —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—O— or    —NR^(x)—C(═O)—Z²—C(═O)—O—. More in particular Y represents    —NR^(x)—C(═O)—Z²—;    or-   D-15) compounds of class D or any subgroup thereof as mentioned    hereinbefore as embodiment wherein Y represents NR^(x)—C(═O)—Z²—;    —NR^(x)—C(═O)—Z²—NR^(y)—; —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—;    —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—O—; —NR^(x)—C(═O)—Z²—O—;    —NR^(x)—C(═O)—Z²—O—C(═O)—; —NR^(x)—C(═O)—Z²—C(═O)—O—;    —NR^(x)—C(═O)—Z²—C(═O)—NR^(y)—;    —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—NR^(y)—; —C(═O)—Z²—;    —C(═O)—NR^(x)—Z²—; —C(═O)—NR^(x)—Z²—O—;    or-   D-16) compounds of class D or any subgroup thereof as mentioned    hereinbefore as embodiment wherein Z² represents C₁₋₆alkanediyl or    C₂₋₆alkenediyl; in particular C₁₋₆alkanediyl; more in particular    methylene;    or-   D-17) compounds of class D or any subgroup thereof as mentioned    hereinbefore as embodiment wherein Z¹ represents C₁₋₆alkanediyl,    optionally substituted with hydroxyl or amino, or wherein two    hydrogen atoms attached to the same carbon atom in C₁₋₆alkanediyl    may optionally be replaced by C₁₋₆alkanediyl; in particular wherein    Z¹ represents C₁₋₆alkanediyl;    or-   D-18) compounds of class D or any subgroup thereof as mentioned    hereinbefore as embodiment wherein R^(x) represents hydrogen;    or-   D-19) compounds of class D or any subgroup thereof as mentioned    hereinbefore as embodiment wherein R^(y) represents hydrogen or    C₁₋₄alkyl or C₂₋₄alkenyl or —S(═O)_(p)-aryl;    or-   D-20) compounds of class D or any subgroup thereof as mentioned    hereinbefore as embodiment wherein R⁸ represents hydrogen;    or-   D-21) compounds of class D or any subgroup thereof as mentioned    hereinbefore as embodiment wherein R⁸ represents halo, C₁₋₄alkyl or    C₁₋₄alkyl substituted with hydroxyl;    or-   D-22) compounds of class D or any subgroup thereof as mentioned    hereinbefore as embodiment wherein aryl represents phenyl or phenyl    substituted with one or two substituents, preferably each    substituent independently selected from halo, C₁₋₆alkyl,    polyhaloC₁₋₆alkyl, C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl or nitro;    or-   D-23) compounds of class D or any subgroup thereof as mentioned    hereinbefore as embodiment wherein Het¹ represents a monocyclic    non-aromatic or aromatic heterocycle or a bicyclic non-aromatic    heterocycle, each of said cycles may optionally be substituted. In    particular Het¹ represents morpholinyl, pyrrolidinyl, piperazinyl,    homopiperazinyl, piperidinyl, furanyl, imidazolyl, thienyl, pyridyl,    1,3-benzodioxolyl, tetrahydropyranyl, each of said heterocycles    optionally being substituted with one or two substituents,    preferably each substituent independently being selected from halo,    C₁₋₆alkyl, C₁₋₆alkyloxycarbonyl, —S(═O)_(p)—C₁₋₄alkyl, aryl,    arylC₁₋₄alkyl, polyhaloC₁₋₆alkyl, C₁₋₆alkyloxy, nitro; more    preferably each substituent independently being selected from halo,    C₁₋₆alkyl, C₁₋₆alkyloxycarbonyl, —S(═O)_(p)—C₁₋₄alkyl, aryl,    arylC₁₋₄alkyl;    or-   D-24) compounds of class D or any subgroup thereof as mentioned    hereinbefore as embodiment wherein aryl¹ represents phenyl,    naphthalenyl or phenyl substituted with one or two substituents,    preferably each substituent independently being selected from    hydroxyl, halo, C₁₋₆alkyl, C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl or    Het;    or-   D-25) compounds of class D or any subgroup thereof as mentioned    hereinbefore as embodiment wherein Het is a monocyclic non-aromatic    or aromatic heterocycle, each of said heterocycles may optionally be    substituted. In particular, Het is piperidinyl, pyrrolidinyl,    piperazinyl, pyridyl, morpholinyl, each of said heterocycles    optionally being substituted with one substituent, preferably the    substituent is selected from C₁₋₆alkyl, C₁₋₆alkyl substituted with    C₁₋₄alkyloxy, —S(═O)_(p)—C₁₋₄alkyl, C₁₋₆alkylcarbonyl;    or-   D-26) compounds of class D or any subgroup thereof as mentioned    hereinbefore as embodiment wherein one or more, preferably all, of    the following restrictions apply:-   a) X represents —NR^(x)—C(═O)—; —Z¹—C(═O)—; —Z¹—NR^(x)—C(═O)—;    —C(═O)—Z¹—; —S(═O)p-; —NR^(x)—C(═S)—;-   b) R² represents C₁₋₆alkyl or R³, with R³ representing phenyl,    naphthalenyl or 1,3-benzodioxolyl, each of said cycles being    optionally substituted with one to five substituents, said    substituents being in particular halo, C₁₋₆alkyl optionally    substituted with hydroxy, polyhaloC₁₋₆alkyl, polyhaloC₁₋₆alkyloxy,    carboxyl, hydroxyl, C₁₋₆alkylcarbonyl, C₁₋₆alkyloxy, C₁₋₆alkylthio,    C₁₋₆alkyloxycarbonyl, nitro, R⁵R⁴N—C₁₋₆alkyl, HetC₁₋₄alkyl.-   c) A represents N;-   d) A represents CH;-   e) Y represents NR^(x)—C(═O)—Z²—; —NR^(x)—C(═O)—Z²—NR^(y);    —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—; —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—O—;    —NR^(x)—C(═O)—Z²—O—; —NR^(x)—C(═O)—Z²—C(═O)—O—;    —NR^(x)—C(═O)—Z²—C(═O)—NR^(y)—;    —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—NR^(y)—; —C(═O)—Z²—;-   f) Z¹ represents C₁₋₆alkanediyl optionally substituted with hydroxy;-   g) R^(y) represents hydrogen; C₁₋₄alkyl optionally substituted with    C₃₋₆cycloalkyl or aryl; C₂₋₄alkenyl; or —S(═O)_(p)-aryl;-   h) aryl¹ represents phenyl, said phenyl optionally substituted with    C₁₋₆alkyl, halo, polyhaloC₁₋₆alkyl, C₁₋₆alkyloxy, nitro,    C₁₋₆alkyloxycarbonyl;-   i) Het¹ represents a 5- or 6-membered non-aromatic or aromatic    heterocycle, such as for example morpholinyl, piperidinyl,    piperazinyl, pyrrolidinyl, furanyl, imidazolyl, thienyl, pyridyl,    said 5- or 6-membered heterocycle optionally substituted with aryl,    C₁₋₆alkyl, arylC₁₋₆alkyl, halo, polyhaloC₁₋₆alkyl,    C₁₋₆alkyloxycarbonyl, —S(═O)₂—C₁₋₄alkyl;    or-   D-27) compounds of class D having the following formula

wherein one or more, preferably all, of the following restrictionsapply:

-   a) A represents CH or N;-   b) X represents —O—C(═O)—; —C(═O)—C(═O)—; —NR^(x)—C(═O)—;    —Z¹—C(═O)—; —Z¹—NR^(x)—C(═O)—; —C(═O)—Z¹—; —S(═O)_(p)—;    —NR^(x)—C(═S)—;-   c) Z¹ represents C₁₋₆alkanediyl; wherein said C₁₋₆alkanediyl may    optionally be substituted with hydroxyl or amino; and wherein two    hydrogen atoms attached to the same carbon atom in C₁₋₆alkanediyl    may optionally be replaced by C₁₋₆alkanediyl;-   d) Y represents NR^(x)—C(═O)—Z²—; —NR^(x)—C(═O)—Z²—NR^(y)—;    —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—; —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—O—;    —NR^(x)—C(═O)—Z²—O—; —NR^(x)—C(═O)—Z²—O—C(═O)—;    —NR^(x)—C(═O)—Z²—C(═O)—O—; —NR^(x)—C(═O)—Z²—C(═O)—NR^(y)—;    —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—NR^(y)—; —C(═O)—Z²—;    —C(═O)—NR^(x)—Z²—; —C(═O)—NR^(x)—Z²—O—;-   e) Z² represents a bivalent radical selected from C₁₋₆alkanediyl,    C₂₋₆alkenediyl or C₂₋₆alkynediyl; wherein each of said    C₁₋₆alkanediyl, C₂₋₆alkenediyl or C₂₋₆alkynediyl may optionally be    substituted with C₁₋₄alkyloxy, C₁₋₄alkylthio, hydroxyl, cyano or    aryl; and wherein two hydrogen atoms attached to the same carbon    atom in the definition of Z² may optionally be replaced by    C₁₋₆alkanediyl;-   f) R^(x) represents hydrogen or C₁₋₄alkyl;-   g) R^(y) represents hydrogen; C₁₋₄alkyl; C₂₋₄alkenyl; or    —S(═O)_(p)-aryl;-   h) R¹ represents C₁₋₁₂alkyl optionally substituted with cyano,    C₁₋₄alkyloxy, C₁₋₄alkyl-oxyC₁₋₄alkyloxy, C₃₋₆cycloalkyl or aryl;    C₂₋₆alkenyl; C₂₋₆alkynyl; C₃₋₆cycloalkyl; adamantanyl; aryl¹; Het¹;    or Het¹C₁₋₆alkyl; provided that when Y represents —NR^(x)—C(═O)—Z²—;    —NR^(x)—C(═O)—Z²—NR^(y); —NR^(x)—C(═O)—Z²—C(═O)—NR^(y)—; —C(═O)—Z²—;    —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—NR^(y)—; —C(═O)—NR^(x)—Z²—;    —C(═O)—NR^(x)—O—Z²—; or —C(═O)—NR^(x)—Z²—NR^(y)—; then R¹ may also    represent hydrogen;-   i) R² represents C₁₋₁₂alkyl or R³;-   j) R³ represents phenyl, naphtalenyl, 2,3-dihydrobenzofuranyl or a    6-membered aromatic heterocycle containing 1 or 2 N atoms, wherein    said phenyl, naphtalenyl, 2,3-dihydrobenzofuranyl or 6-membered    aromatic heterocycle containing 1 or 2 N atoms may optionally be    substituted with at least one substituent, in particular one, two,    three, four or five substituents, each substituent independently    selected from hydroxyl; carboxyl; halo; C₁₋₆alkyl optionally    substituted with hydroxy; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy;    C₁₋₆alkylthio; polyhalo-C₁₋₆alkyloxy; C₁₋₆alkyloxycarbonyl;    C₁₋₆alkylcarbonyl; nitro; R⁵R⁴N—C(═O)—; R⁵R⁴N—C₁₋₆alkyl;    HetC₁₋₄alkyl; Het-C(═O)—C₁₋₄alkyl; Het-C(═O)—;-   k) R⁴ represents hydrogen; C₁₋₄alkyl optionally substituted with    hydroxyl or C₁₋₄alkyloxy; R⁷R⁶N—C₁₋₄alkyl; Het-C₁₋₄alkyl;    R⁷R⁶N—C(═O)—C₁₋₄alkyl;-   l) R⁵ represents hydrogen or C₁₋₄alkyl;-   m) R⁶ represents C₁₋₄alkyl or C₁₋₄alkylcarbonyl;-   n) R⁷ represents hydrogen or C₁₋₄alkyl; or-   o) R⁶ and R⁷ may be taken together with the nitrogen to which they    are attached to form a saturated monocyclic 5, 6 or 7-membered    heterocycle which may further contain one or more heteroatoms each    independently selected from O or N;-   p) R⁸ represents hydrogen, halo, C₁₋₄alkyl substituted with    hydroxyl;-   q) aryl represents phenyl or phenyl substituted with at least one    substituent, in particular one or two substituents, each substituent    independently being selected from halo; C₁₋₆alkyl;    polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy; nitro;-   r) aryl¹ represents phenyl or naphthalenyl; wherein phenyl may    optionally be substituted with one or two substituents, each    substituent independently being selected from hydroxyl; halo;    C₁₋₆alkyl; C₁₋₆alkyloxy; C₁₋₆alkyloxy-carbonyl or Het;-   s) Het represents a monocyclic non-aromatic or aromatic heterocycle    containing at least one heteroatom each independently selected from    O, S, S(═O)_(p) or N, in particular N; said monocyclic heterocycle    optionally being substituted with one substituent, said substituent    being selected from C₁₋₆alkyl optionally substituted with    C₁₋₄alkyloxy; C₁₋₆alkylcarbonyl or —S(═O)_(p)—C₁₋₄alkyl;-   t) Het¹ represents a monocyclic non-aromatic or aromatic heterocycle    containing at least one heteroatom each independently selected from    O, S, S(═O)_(p) or N, in particular N, O or S; or a bicyclic    non-aromatic heterocycle containing at least one heteroatom each    independently selected from O, S, S(═O)_(p) or N, in particular O;    said monocyclic heterocycle or said bicyclic heterocycle optionally    being substituted with one or two substituents, each substituent    independently being selected from halo; C₁₋₆alkyl;    C₁₋₆alkyloxy-carbonyl; —S(═O)_(p)—C₁₋₄alkyl; aryl; or arylC₁₋₄alkyl;-   u) p represents 2;    or-   D-28) compounds of class D selected from

including any stereochemically isomeric form thereof;

-   a N-oxide thereof, a pharmaceutically acceptable salt thereof or a    solvate thereof.    or-   D-29) compounds of class D selected from

including any stereochemically isomeric form thereof;

-   a N-oxide thereof, a pharmaceutically acceptable salt thereof or a    solvate thereof.    or-   D-30) compounds of class D selected from:-   N-[4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]phenyl]-4-methoxy-benzeneacetamide    (compound 355 Class D);-   4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide    (compound 354 Class D);-   4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]hydroxyacetyl]-1-piperazinyl]-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide    (compound 356 Class D);-   4-[4-[[2,6-dichloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide    (compound 358 Class D);-   4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide    (compound 353 Class D);-   4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]hydroxyacetyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide    (compound 357 Class D);-   4-[4-[[2,6-dichloro-4-[(4-ethyl-1-piperazinyl)methyl]phenyl]acetyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide    (compound 360 Class D);-   4-[4-[[2,6-dichloro-4-[(4-ethyl-1-piperazinyl)methyl]phenyl]acetyl]-1-piperazinyl]-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide    (compound 359 Class D);-   4-[4-[[2,6-dichloro-4-[[4-(methylsulfonyl)-1-piperazinyl]methyl]phenyl]acetyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide    (compound 364 Class D);-   4-[4-[[4-[(4-acetyl-1-piperazinyl)methyl]-2,6-dichlorophenyl]acetyl]-1-piperazinyl]-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide    (compound 361 Class D);-   4-[4-[[2,6-dichloro-4-[[4-(methylsulfonyl)-1-piperazinyl]methyl]phenyl]acetyl]-1-piperazinyl]-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide    (compound 363 Class D);-   4-[4-[[4-[(4-acetyl-1-piperazinyl)methyl]-2,6-dichlorophenyl]acetyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide    (compound 362 Class D);-   N-[4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]hydroxyacetyl]-1-piperazinyl]phenyl]-4-methoxy-benzeneacetamide    (compound 352 Class D);-   N-[4-[4-[[2,6-dichloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]phenyl]-4-methoxy-benzeneacetamide    (compound 351 Class D);-   4-[4-[[2,6-dichloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide    (compound 267 Class D);    including any stereochemically isomeric form thereof;    a N-oxide thereof, a pharmaceutically acceptable salt thereof or a    solvate thereof.

In an embodiment, the present invention also relates to a combination of

including any stereochemically isomeric form thereof;a N-oxide thereof, a pharmaceutically acceptable salt thereof or asolvate thereof; and fenofibrate.

In an embodiment, the present invention also relates to a combination of4-[4-[[2,6-dichloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide(compound 358 Class D), including any stereochemically isomeric formthereof; a N-oxide thereof, a pharmaceutically acceptable salt thereofor a solvate thereof; and fenofibrate.

General Preparation

I) Class A compounds

The general preparation of the compounds of Class A is described inWO2008/148851, the content of which is enclosed by reference in thepresent application.

II) Class B compounds

The general preparation of the compounds of Class B is described inWO2008/148840, the content of which is enclosed by reference in thepresent application.

III) Class C compounds

The general preparation of the compounds of Class C is described inWO2008/148849, the content of which is enclosed by reference in thepresent application.

IV) Class D compounds

The general preparation of the compounds of Class D is described inWO2008/148868, the content of which is enclosed by reference in thepresent application.

In addition to the general procedures described in WO2008/148868,intermediates of Class D of formula (XI) can also be prepared from anintermediate of formula (LXIV) in the presence of an acid such as, forexample, an HCl solution. The reaction may be performed in the presenceof a suitable solvent such as, for example, dioxane. Intermediates offormula (LXIV) wherein R² contains Het-C₁₋₄alkyl as substituent (Het isdefined as a saturated N-containing heterocycle such as, for example,pyrrollidinyl) and wherein X₁ is a direct bond, said intermediates beingrepresented by formula (LXIV-a) can be prepared by reacting anintermediate of formula (LXV) in het presence of a saturatedN-containing heterocycle such as, for example, pyrrolidine, and water.Intermediates of formula (LXV) can be prepared by reacting anintermediate of formula (LXII) wherein R² contains Het-C₁₋₄alkyl assubstituent, hereby named (LXII-a), in the presence of tetrabromomethaneand a catalyst such as, for example, triphenylphosphine. This reactioncan be performed in a suitable solvent such as, for example, DCM.

Pharmacological Part

As already indicated above, the present invention relates to the use ofa drug combination comprising a DGAT inhibitor and a PPAR agonist or aprodrug thereof, as a medicament.

In particular, the present invention relates to the use of a drugcombination comprising a DGAT inhibitor and a PPAR-α agonist or aprodrug thereof, as a medicament.

In particular, the present invention relates to the use of a drugcombination comprising a DGAT1 inhibitor and a PPAR-α agonist or aprodrug thereof, as a medicament.

In particular, the combinations according to the present invention aresuitable for reducing food intake, for reducing weight, for suppressingappetite, for inducing satiety; or for the treatment or prevention, inparticular treatment, of metabolic disorders, such as obesity and/orobesity related disorders (including, but not limited to, peripheralvascular disease, cardiac failure, myocardial ischaemia, cerebralischaemia, cardiac myopathies), diabetes, in particular type II diabetesmellitus, and/or complications arising therefrom (such as retinopathy,neuropathy, nephropathy), syndrome X, insulin resistance, impairedglucose tolerance, conditions of impaired fasting glucose, hypoglycemia,hyperglycemia, hyperuricemia, hyperinsulinemia, pancreatitis,hypercholesterolemia, hyperlipidemia, dyslipidemia, mixed dyslipidemia,hypertriglyceridemia, nonalcoholic fatty liver disease, fatty liver,increased mesenteric fat, non-alcoholic steatohepatitis, liver fibrosis,metabolic acidosis, ketosis, dysmetabolic syndrome; dermatologicalconditions such as acne, psoriasis; cardiovascular diseases, such asatherosclerosis, arteriosclerosis, acute heart failure, congestive heartfailure, coronary artery disease, cardiomyopathy, myocardial infarction,angina pectoris, hypertension, hypotension, stroke, ischemia, ischemicreperfusion injury, aneurysm, restenosis or vascular stenosis;alzheimer's disease; neoplastic diseases, such as solid tumors, skincancer, melanoma, lymphoma or endothelial cancers, e.g., breast cancer,lung cancer, colorectal cancer, stomach cancer, other cancers of thegastrointestinal tract (e.g., esophageal cancer or pancreatic cancer),prostate cancer, kidney cancer, liver cancer, bladder cancer, cervicalcancer, uterine cancer, testicular cancer or ovarian cancer.

In an embodiment, the combinations according to the present inventionare suitable for reducing food intake, for reducing weight, forsuppressing appetite, for inducing satiety; or for the treatment orprevention, in particular treatment, of metabolic disorders, such asobesity and/or obesity related disorders (including, but not limited to,peripheral vascular disease, cardiac failure, myocardial ischaemia,cerebral ischaemia, cardiac myopathies), diabetes, in particular type IIdiabetes mellitus, and/or complications arising therefrom (such asretinopathy, neuropathy, nephropathy), syndrome X, insulin resistance,impaired glucose tolerance, conditions of impaired fasting glucose,hypoglycemia, hyperglycemia, hyperuricemia, hyperinsulinemia,pancreatitis, hypercholesterolemia, hyperlipidemia, dyslipidemia, mixeddyslipidemia, hypertriglyceridemia, nonalcoholic fatty liver disease,fatty liver, increased mesenteric fat, non-alcoholic steatohepatitis,liver fibrosis, metabolic acidosis, ketosis, dysmetabolic syndrome;dermatological conditions such as acne, psoriasis; cardiovasculardiseases, such as atherosclerosis, arteriosclerosis, acute heartfailure, congestive heart failure, coronary artery disease,cardiomyopathy, myocardial infarction, angina pectoris, hypertension,hypotension, stroke, ischemia, ischemic reperfusion injury, aneurysm,restenosis or vascular stenosis.

In an embodiment, the combinations according to the present inventionare suitable for reducing food intake, for reducing weight, forsuppressing appetite, for inducing satiety; or for the treatment orprevention, in particular treatment, of obesity and/or obesity relateddisorders, hypercholesterolemia, hyperlipidemia, dyslipidemia, mixeddyslipidemia, hypertriglyceridemia, fatty liver, nonalcoholic fattyliver disease, liver fibrosis, non-alcoholic steatohepatitis ordiabetes.

In an embodiment, the combinations according to the present inventionare suitable for reducing food intake, for reducing weight, forsuppressing appetite, for inducing satiety; for the treatment orprevention of obesity and/or obesity related disorders, obesity orcardiovascular diseases.

In an embodiment, said obesity related disorder is selected fromperipheral vascular disease, cardiac failure, myocardial ischaemia,cerebral ischaemia or cardiac myopathies.

In an embodiment, the combinations according to the present inventionare suitable for reducing food intake and/or for reducing weight.

In an embodiment, the combinations according to the present inventionare suitable for reducing food intake.

In an embodiment, the combinations according to the present inventionare suitable for the treatment of said diseases or conditions.

In an embodiment, the combinations according to the present inventionare suitable for use in the treatment or prevention, in particulartreatment, of said diseases or conditions.

In an embodiment, the combinations according to the present inventionare suitable for the manufacture of a medicament; in particular amedicament for the treatment or prevention, in particular the treatment,of the diseases or conditions mentioned hereinbefore.

The present invention also relates to a product containing a) a DGATinhibitor, in particular a DGAT1 inhibitor, more in particular acompound of Class A, Class B, Class C or Class D, and (b) an agonist ofperoxisome proliferators-activator receptor or a prodrug thereof such asfor example fenofibrate, as a combined preparation for simultaneous,separate or sequential use in the treatment of a disease which canbenefit from an elevated level of GLP-1 or DGAT inhibition, such as forexample diabetes, in particular type II diabetes mellitus, obesity, forsuppressing appetite, inducing satiety or for reducing food intake.

In view of the utility of the combinations of the present invention,there is provided a method of treating warm-blooded animals, includinghumans, suffering from or a method of preventing warm-blooded animals,including humans, to suffer from any one of the diseases or conditionsmentioned hereinbefore.

Said methods comprise the administration, i.e. the systemic or topicaladministration, preferably oral administration, of an effective amountof an above mentioned combination to warm-blooded animals, includinghumans.

Those of skill in the treatment of such diseases could determine theeffective therapeutic daily amount from the test results presentedhereinafter. An effective therapeutic daily amount of a combination ofPPAR agonist (or prodrug thereof)/DGAT inhibitor would be from about0.01 mg/kg to 250 mg/kg body weight, preferably from 0.01 mg/kg to 50mg/kg body weight, more preferably from about 0.01 mg/kg to about 10mg/kg, even more preferably from about 0.05 mg/kg to about 1 mg/kg bodyweight. The amount of a compound according to the present invention,also referred to here as the active ingredient, which is required toachieve a therapeutically effect will of course, vary on case-by-casebasis, for example with the particular compound, the route ofadministration, the age and condition of the recipient, and theparticular disorder or disease being treated.

A method of treatment may also include administering the activeingredient on a regimen of between one and four intakes per day. Inthese methods of treatment the compounds according to the invention arepreferably formulated prior to administration. As described hereinbelow, suitable pharmaceutical formulations are prepared by knownprocedures using well known and readily available ingredients.

In an embodiment, the present invention also relates to pharmaceuticalcompositions comprising a pharmaceutically acceptable carrier, and asactive ingredient a therapeutically effective amount of the combinationsmentioned hereinbefore or hereinafter.

The combinations of the present invention may be formulated into variouspharmaceutical forms for administration purposes. As appropriatecompositions there may be cited all compositions usually employed forsystemically administering drugs. To prepare the pharmaceuticalcompositions of this invention, an effective amount of the particularcombination, as the active ingredient, is combined in intimate admixturewith a pharmaceutically acceptable carrier, which carrier may take awide variety of forms depending on the form of preparation desired foradministration. These pharmaceutical compositions are desirable inunitary dosage form suitable, particularly, for administration orally,rectally, percutaneously, or by parenteral injection. For example, inpreparing the compositions in oral dosage form, any of the usualpharmaceutical media may be employed such as, for example, water,glycols, oils, alcohols and the like in the case of oral liquidpreparations such as suspensions, syrups, elixirs, emulsions andsolutions; or solid carriers such as starches, sugars, kaolin, diluents,lubricants, binders, disintegrating agents and the like in the case ofpowders, pills, capsules, and tablets. Because of their ease inadministration, tablets and capsules represent the most advantageousoral dosage unit forms, in which case solid pharmaceutical carriers areobviously employed. For parenteral compositions, the carrier willusually comprise sterile water, at least in large part, though otheringredients, for example, to aid solubility, may be included. Injectablesolutions, for example, may be prepared in which the carrier comprisessaline solution, glucose solution or a mixture of saline and glucosesolution. Injectable suspensions may also be prepared in which caseappropriate liquid carriers, suspending agents and the like may beemployed. Also included are solid form preparations, which are intendedto be converted, shortly before use, to liquid form preparations. In thecompositions suitable for percutaneous administration, the carrieroptionally comprises a penetration enhancing agent and/or a suitablewetting agent, optionally combined with suitable additives of any naturein minor proportions, which additives do not introduce a significantdeleterious effect on the skin. Said additives may facilitate theadministration to the skin and/or may be helpful for preparing thedesired compositions. These compositions may be administered in variousways, e.g., as a transdermal patch, as a spot-on, as an ointment.

The combinations of the present invention may also be administered viainhalation or insufflation by means of methods and formulations employedin the art for administration via this way. Thus, in general thecompounds of the present invention may be administered to the lungs inthe form of a solution, a suspension or a dry powder. Any systemdeveloped for the delivery of solutions, suspensions or dry powders viaoral or nasal inhalation or insufflation are suitable for theadministration of the present compounds.

The combinations of the present invention may also be topicallyadministered in the form of drops, in particular eye drops. Said eyedrops may be in the form of a solution or a suspension. Any systemdeveloped for the delivery of solutions or suspensions as eye drops aresuitable for the administration of the present compounds.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in unit dosage form for ease ofadministration and uniformity of dosage. Unit dosage form as used hereinrefers to physically discrete units suitable as unitary dosages, eachunit containing a predetermined quantity of active ingredient calculatedto produce the desired therapeutic effect in association with therequired pharmaceutical carrier. Examples of such unit dosage forms aretablets (including scored or coated tablets), capsules, pills, powderpackets, wafers, suppositories, injectable solutions or suspensions andthe like, and segregated multiples thereof.

The exact dosage and frequency of administration depends on theparticular combination of the present invention used, the particularcondition being treated, the severity of the condition being treated,the age, weight, sex, extent of disorder and general physical conditionof the particular patient as well as other medication the individual maybe taking, as is well known to those skilled in the art. Furthermore, itis evident that said effective daily amount may be lowered or increaseddepending on the response of the treated subject and/or depending on theevaluation of the physician prescribing the combinations of the instantinvention.

Depending on the mode of administration, the pharmaceutical compositionwill preferably comprise from 0.05 to 99% by weight, more preferablyfrom 0.1 to 70% by weight, even more preferably from 0.1 to 50% byweight of the combination of PPAR agonist/DGAT inhibitor, and, from 1 to99.95% by weight, more preferably from 30 to 99.9% by weight, even morepreferably from 50 to 99.9% by weight of a pharmaceutically acceptablecarrier, all percentages being based on the total weight of thecomposition.

In all previous embodiments, the different drugs of a combination orproduct may be combined in a single preparation together withpharmaceutically acceptable carriers or they may be present in aseparate preparation together with pharmaceutically acceptable carriers.

As already indicated above, the present invention also relates to theuse of the novel DGAT inhibitors of group Q, in particular DGAT1inhibitors of group Q, to elevate levels of one or more satietyhormones, in particular GLP-1 levels. The present invention also relatesto the use of a DGAT inhibitor of group Q, in particular a novel DGAT1inhibitor of group Q, for the manufacture of a medicament for theprevention or the treatment, in particular for the treatment, of adisease which can benefit from an elevated level of one or more satietyhormones, in particular a disease which can benefit from an elevatedGLP-1 level. In particular, GLP-1 levels are elevated in plasma or inportal blood, more in particular in plasma. By elevated GLP-1 levels,e.g. elevated GLP-1 plasma level or an elevated GLP-1 level in portalblood, it is meant that the GLP-1 level of a subject having taken aDGAT1 inhibitor is elevated or increased compared to the subject underthe same conditions but not having taken the DGAT1 inhibitor. Inparticular GLP-1 levels are elevated in fasting conditions orpostprandial, more in particular postprandial.

Therapeutic uses for a compound which elevates GLP-1 level include, butare not limited to, improving learning, enhancing neuro-protection,and/or alleviating a symptom of a disease or disorder of the centralnervous system, e.g., through modulation of neurogenesis, and e.g.,Parkinson's Disease, Alzheimer's Disease, Huntington's Disease, ALS,stroke, hemorrhage, cerebrovascular accident, ADD, and neuropsychiatricsyndromes; converting liver stem/progenitor cells into functionalpancreatic cells; preventing beta-cell deterioration and stimulation ofbeta-cell proliferation; treating pancreatitis; treating obesity;suppressing appetite and inducing satiety; treating irritable bowelsyndrome or inflammatory bowel disease such as Crohn's disease andulcerative colitis; reducing the morbidity and/or mortality associatedwith myocardial infarction and stroke; treating acute coronary syndromecharacterized by an absence of Q-wave myocardial infarction; attenuatingpost-surgical catabolic changes; treating hibernating myocardium ordiabetic cardiomyopathy; suppressing plasma blood levels ofnorepinepherine; increasing urinary sodium excretion, decreasing urinarypotassium concentration; treating conditions or disorders associatedwith toxic hypervolemia, e.g., renal failure, congestive heart failure,nephrotic syndrome, cirrhosis, pulmonary edema, and hypertension;inducing an inotropic response and increasing cardiac contractility;treating polycystic ovary syndrome; treating respiratory distress;improving nutrition via a non-alimentary route, i.e., via intravenous,subcutaneous, intramuscular, peritoneal, or other injection or infusion;treating nephropathy; treating left ventricular systolic dysfunction,e.g., with abnormal left ventricular ejection fraction; inhibitingantro-duodenal motility, e.g., for the treatment or prevention ofgastrointestinal disorders such as diarrhea, postoperative dumpingsyndrome and irritable bowel syndrome, and as premedication inendoscopic procedures; treating critical illness polyneuropathy (CIPN)and systemic inflammatory response syndrome (SIRS); modulatingtriglyceride levels and treating dyslipidemia; treating organ tissueinjury (e.g. brain tissue injury) caused by reperfusion of blood flowfollowing ischemia; improving the function of ischemic and reperfusedbrain tissue; treating coronary heart disease risk factor (CHDRF)syndrome. Further diseases which can benefit from an elevated GLP-1level, include, but are not limited to, ischemic myocardial stunning;ishemic/reperfusion injury; acute myocardial infarction; leftventricular dysfunction; vascular disease; neuropathy, includingperiphere sensoric neuropathy associated with type II diabetes;bone-related disorders, including osteoporosis, obesity, diabetes.Because of the effect on GLP-1, the DGAT inhibitors of group Q can alsobe used to provide cardioprotection.

References supporting the above indications include ExperimentalNeurology, Vol. 203(2), pp 293-301 (2007); U.S. Pat. No. 7,186,683; J.Pharm. Exp. Ther vol. 312, No. 1, pp 303-308 (2005); Diabetes, vol. 54,pp 146-151 (2005); US2007/0021339, which are incorporated herein byreference.

In view of the DGAT inhibitory activity, in particular the DGAT1inhibitory activity, the present novel compounds of group Q can be usedas a medicament. In particular, the present invention relates to acompound of group Q for use as a medicament, in particular for use as amedicament for the prevention or the treatment of a disease which canbenefit from an elevated GLP-1 level. In particular, the presentinvention also relates to the use of a compound of group Q for themanufacture of a medicament for the prevention or the treatment of adisease which can benefit from an elevated GLP-1 level, such as thediseases and disorders mentioned above.

In view of the DGAT inhibitory activity of the compounds of group Q,there is provided a method of treating a warm-blooded mammal, includinga human, suffering from or a method of preventing a warm-blooded mammal,including a human, to suffer from a disease which can benefit from anelevated level of GLP-1, in particular a method of treating awarm-blooded mammal, including a human, suffering from a disease whichcan benefit from an elevated level of GLP-1. Said methods comprise theadministration of an effective amount of a compound of group Q to awarm-blooded mammal, including a human.

In view of the DGAT inhibitory activity, in particular the DGAT1inhibitory activity, the present invention also relates to a compound ofgroup Q for use as a medicament, in particular for use as a medicamentfor the prevention or the treatment of a diseases which can benefit frominhibition of DGAT, in particular DGAT1.

The invention also relates to a compound of group Q for the preventionor the treatment of a disease or disorder which can benefit frominhibition of DGAT, in particular DGAT1. Diseases or disorders which canbenefit from inhibition of DGAT, in particular DGAT1 include, but arenot limited to metabolic disorders, such as obesity and/or obesityrelated disorders (including peripheral vascular disease, cardiacfailure, myocardial ischaemia, cerebral ischaemia, cardiac myopathies),diabetes, in particular type II diabetes mellitus, and/or complicationsarising therefrom (such as retinopathy, neuropathy, nephropathy),syndrome X, insulin resistance, impaired glucose tolerance, conditionsof impaired fasting glucose, hypoglycemia, hyperglycemia, hyperuricemia,hyperinsulinemia, pancreatitis, hypercholesterolemia, hyperlipidemia,dyslipidemia, mixed dyslipidemia, hypertriglyceridemia, nonalcoholicfatty liver disease, fatty liver, increased mesenteric fat,non-alcoholic steatohepatitis, liver fibrosis, metabolic acidosis,ketosis, dysmetabolic syndrome; dermatological conditions such as acne,psoriasis; cardiovascular diseases, such as atherosclerosis,arteriosclerosis, acute heart failure, congestive heart failure,coronary artery disease, cardiomyopathy, myocardial infarction, anginapectoris, hypertension, hypotension, stroke, ischemia, ischemicreperfusion injury, aneurysm, restenosis or vascular stenosis;neoplastic diseases, such as solid tumors, skin cancer, melanoma,lymphoma or endothelial cancers, e.g., breast cancer, lung cancer,colorectal cancer, stomach cancer, other cancers of the gastrointestinaltract (e.g., esophageal cancer and pancreatic cancer), prostate cancer,kidney cancer, liver cancer, bladder cancer, cervical cancer, uterinecancer, testicular cancer or ovarian cancer; or other diseases andconditions that are sensitive or responsive to modulation, in particularinhibition, of DGAT function, in particular DGAT1 function.

Particular diseases or disorders which can benefit from inhibition ofDGAT, in particular DGAT1, are selected from obesity,hypercholesterolemia, hyperlipidemia, dyslipidemia, mixed dyslipidemia,hypertriglyceridemia, fatty liver, nonalcoholic fatty liver disease,liver fibrosis, non-alcoholic steatohepatitis or diabetes, in particulartype II diabetes.

The invention also relates to a compound of group Q for use in theprevention or the treatment, in particular for use in the treatment, ofa disease or disorder which can benefit from inhibition of DGAT, inparticular DGAT1.

In an embodiment the invention also relates to the use of a compound ofgroup Q for the manufacture of a medicament for treating or preventingthe above mentioned diseases or conditions.

In view of the DGAT inhibitory activity of the compounds of group Q,there is provided a method of treating a warm-blooded mammal, includinga human, suffering from or a method of preventing a warm-blooded mammal,including a human, to suffer from a disease which can benefit frominhibition of DGAT, in particular a method of treating a warm-bloodedmammal, including a human, suffering from a disease which can benefitfrom inhibition of DGAT. Said methods comprise the administration of aneffective amount of a compound of group Q to a warm-blooded mammal,including a human.

In an embodiment, the present invention also relates to pharmaceuticalcompositions comprising a pharmaceutically acceptable carrier, and asactive ingredient a therapeutically effective amount of a compound ofgroup Q.

The present invention also provides compositions for preventing ortreating a disease which can benefit from an elevated GLP-1 level orwhich can benefit from inhibition of DGAT, in particular DGAT1, inparticular for treating a disease which can benefit from elevated GLP-1levels or which can benefit from inhibition of DGAT, in particularDGAT1. Said compositions comprise a therapeutically effective amount ofa compound of group Q and a pharmaceutically acceptable carrier.

The novel compounds of group Q of the present invention may beformulated into various pharmaceutical forms for administrationpurposes. As appropriate compositions there may be cited allcompositions usually employed for systemically administering drugs. Toprepare the pharmaceutical compositions of this invention, an effectiveamount of the particular compound, optionally in salt form, as theactive ingredient is combined in intimate admixture with apharmaceutically acceptable carrier, which carrier may take a widevariety of forms depending on the form of preparation desired foradministration. These pharmaceutical compositions are desirable inunitary dosage form suitable, particularly, for administration orally,rectally, percutaneously, or by parenteral injection. For example, inpreparing the compositions in oral dosage form, any of the usualpharmaceutical media may be employed such as, for example, water,glycols, oils, alcohols and the like in the case of oral liquidpreparations such as suspensions, syrups, elixirs, emulsions andsolutions; or solid carriers such as starches, sugars, kaolin, diluents,lubricants, binders, disintegrating agents and the like in the case ofpowders, pills, capsules, and tablets. Because of their ease inadministration, tablets and capsules represent the most advantageousoral dosage unit forms, in which case solid pharmaceutical carriers areobviously employed. For parenteral compositions, the carrier willusually comprise sterile water, at least in large part, though otheringredients, for example, to aid solubility, may be included. Injectablesolutions, for example, may be prepared in which the carrier comprisessaline solution, glucose solution or a mixture of saline and glucosesolution. Injectable suspensions may also be prepared in which caseappropriate liquid carriers, suspending agents and the like may beemployed. Also included are solid form preparations, which are intendedto be converted, shortly before use, to liquid form preparations. In thecompositions suitable for percutaneous administration, the carrieroptionally comprises a penetration enhancing agent and/or a suitablewetting agent, optionally combined with suitable additives of any naturein minor proportions, which additives do not introduce a significantdeleterious effect on the skin. Said additives may facilitate theadministration to the skin and/or may be helpful for preparing thedesired compositions. These compositions may be administered in variousways, e.g., as a transdermal patch, as a spot-on, as an ointment.

The compounds of group Q of the present invention may also beadministered via inhalation or insufflation by means of methods andformulations employed in the art for administration via this way. Thus,in general the compounds of the present invention may be administered tothe lungs in the form of a solution, a suspension or a dry powder. Anysystem developed for the delivery of solutions, suspensions or drypowders via oral or nasal inhalation or insufflation are suitable forthe administration of the present compounds.

The compounds of the present invention may also be topicallyadministered in the form of drops, in particular eye drops. Said eyedrops may be in the form of a solution or a suspension. Any systemdeveloped for the delivery of solutions or suspensions as eye drops aresuitable for the administration of the present compounds.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in unit dosage form for ease ofadministration and uniformity of dosage. Unit dosage form as used hereinrefers to physically discrete units suitable as unitary dosages, eachunit containing a predetermined quantity of active ingredient calculatedto produce the desired therapeutic effect in association with therequired pharmaceutical carrier. Examples of such unit dosage forms aretablets (including scored or coated tablets), capsules, pills, powderpackets, wafers, suppositories, injectable solutions or suspensions andthe like, and segregated multiples thereof.

The exact dosage and frequency of administration depends on theparticular compound of group Q used, the particular condition beingtreated, the severity of the condition being treated, the age, weight,sex, extent of disorder and general physical condition of the particularpatient as well as other medication the individual may be taking, as iswell known to those skilled in the art. Furthermore, it is evident thatsaid effective daily amount may be lowered or increased depending on theresponse of the treated subject and/or depending on the evaluation ofthe physician prescribing the compounds of the instant invention.

Depending on the mode of administration, the pharmaceutical compositionwill preferably comprise from 0.05 to 99% by weight, more preferablyfrom 0.1 to 70% by weight, even more preferably from 0.1 to 50% byweight of the compound of group Q, and, from 1 to 99.95% by weight, morepreferably from 30 to 99.9% by weight, even more preferably from 50 to99.9% by weight of a pharmaceutically acceptable carrier, allpercentages being based on the total weight of the composition.

The following examples are intended to illustrate the present invention.

Experimental Part

Hereinafter, the term ‘THF’ means tetrahydrofuran, ‘Et₂O’ means diethylether, ‘CH₃OH’ means methanol, ‘EtOAc’ means ethyl acetate, ‘NaHCO₃’means carbonic acid monosodium salt, ‘CH₂Cl₂’ or ‘DCM’ meansdichloromethane, ‘CH₃CN’ means acetonitrile, ‘EtOH’ means ethanol,‘HBTU’ means1-[bis(di-methylamino)methylene]-1H-benzo-triazoliumhexafluorophosphate(1-)-3-oxide,‘DMF’ means N,N-dimethyl-formamide, ‘DIPEA’ meansN-ethyl-N-(1-methylethyl)-2-propanamine, ‘HOBt’ or ‘HOBT’ means1-hydroxy-1H-benzotriazole, ‘EDCI’ meansN-(ethylcarbonimidoyl)-N,N-dimethyl-1,3-propanediaminemonohydrochloride, ‘DMSO’ means dimethylsulfoxide, ‘m.p.’ means meltingpoint, ‘MeOH’ means methanol, ‘Et₃N’ means triethylamine, ‘eq.’ meansequivalent, ‘r.m.’ means reaction mixture, ‘r.t.’ means roomtemperature, ‘h’ means hour(s), ‘min’ means minute(s), and ‘TFA’ meanstrifluoroacetic acid.

Experimental Procedures for the Class A Compounds

The experimental procedures for the preparation of the compounds ofClass A, are described in WO2008/148851, the content of which isenclosed by reference in the present application.

Experimental procedures for the Class B compounds

The experimental procedures for the preparation of the compounds ofClass B, are described in WO2008/148840, the content of which isenclosed by reference in the present application.

Experimental procedures for the Class C compounds

The experimental procedures for the preparation of the compounds ofClass C, are described in WO2008/148849, the content of which isenclosed by reference in the present application.

In addition, some typical examples of Class C compounds are describedbelow.

Intermediates Class C Preparation of4-(1-piperazinyl)-N-[3-(1-pyrrolidinyl)phenyl]-benzamide and4-(1-piperazinyl)-N-[3-(1-pyrrolidinyl)phenyl]-benzamide .HCl.

Pd/C 10% (1 g) was suspended in MeOH (150 ml) under N₂ flow.4-[4-(phenylmethyl)-1-piperazinyl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide(5.62 g, 0.0126 mol; prepared according to the teachings described inWO2008/148849) was added and the r.m. was stirred at 50° C. under H₂atmosphere until 1 eq. of H₂ was absorbed. The catalyst was filtered offover diatomaceous earth (Dicalite®). The solvent was evaporated andco-evaporated with toluene. The residue was stirred in Et₂O and filteredoff. The product was dried (50° C., 18 h, in vacuo). Yield: 4.23 g of4-(1-piperazinyl)-N-[3-(1-pyrrolidinyl)phenyl]-benzamide (96%).

4-(1-piperazinyl)-N-[3-(1-pyrrolidinyl)phenyl]-benzamide .HCl wasprepared in analogy to the free base form. For the preparation of thehydrochloric acid salt,4-[4-[[[3-(1-pyrrolidinyl)phenyl]amino]carbonyl]phenyl]-1-piperazinecarboxylicacid, 1,1-dimethylethyl ester (the tert-butoxy variant of4-[4-(phenylmethyl)-1-piperazinyl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide)was deprotected with a HCl solution in dioxane.

Preparation of 1-[(4-bromo-3-chlorophenyl)methyl]-pyrrolidine

A solution of 1-bromo-2-chloro-4-(chloromethyl)-benzene (25.2 g, 105.03mmol) and Et₃N (16.1 ml, 115.53 mmol) in THF (150 ml) was stirred atr.t. Pyrrolidine (8.2 g, 115.53 mmol) was added dropwise. The r.m. wasstirred overnight at r.t. and was then concentrated in vacuo. Theresidue was taken up into water and extracted with CH₂Cl₂ (3×100 ml).The combined organic layer was washed with saturated NaHCO₃ and brine,and was then dried (MgSO₄), filtered and the solvent was evaporated invacuo. Yield: 25.8 g of 1-[(4-bromo-3-chlorophenyl)methyl]-pyrrolidine(90% yield, crude product; used in next reaction step, without furtherpurification).

Preparation of 2-chloro-4-(1-pyrrolidinylmethyl)-benzaldehyde

Reaction under N₂ atmosphere. A solution of1-[(4-bromo-3-chlorophenyl)methyl]-pyrrolidine (25.8 g, 93.96 mmol) inTHF (200 ml) was stirred at −78° C. for 15 min A 2.5 M n-BuLi solutionin hexane was added to the mixture over a period of 15 min. After 30min, a solution of DMF (7.3 ml, 93.96 mmol) in THF (50 ml) was addeddropwise to the mixture. The reaction temperature was allowed to rise tor.t. slowly, and the mixture was stirred overnight. The reaction wasquenched by the addition of water at 0° C. The mixture was extractedwith EtOAc (3×150 ml). The combined organic layer was washed with brine,dried (MgSO₄), filtered and the solvent was evaporated in vacuo.

Yield: 20.3 g of 2-chloro-4-(1-pyrrolidinylmethyl)-benzaldehyde (97%,crude Yield:). The crude product was used for next step directly withoutfurther purification.

Preparation of2-chloro-α-hydroxy-4-(1-pyrrolidinylmethyl)-benzeneacetonitrile

Trimethylsilanecarbonitrile (10 ml, 76.6 mmol) and ZnBr₂ (0.5 g) wereadded to a solution of 2-chloro-4-(1-pyrrolidinylmethyl)-benzaldehyde(9.8 g, 43.8 mmol) in DCM (100 ml). The r.m. was stirred for 5 h at r.t.Then, the mixture was heated to 50° C. and stirred overnight.2-chloro-α-hydroxy-4-(1-pyrrolidinylmethyl)-benzeneacetonitrile was usedas a crude in the next reaction step.

Preparation of 2-chloro-α-hydroxy-4-(1-pyrrolidinylmethyl)-benzeneaceticacid (TFA-salt)

A mixture of2-chloro-α-hydroxy-4-(1-pyrrolidinylmethyl)-benzeneacetonitrile (10.9 g,43.8 mmol) in concentrated HCl (50 ml) was stirred and refluxed for 24h. The mixture was cooled and the solvent was evaporated. The crudeproduct was purified by preparative HPLC (Synergi: 250×20 mm; MobilePhase: 0-30% CH₃CN in H₂O (0.1% TFA); Flow Rate: 80 ml/min; FinishedTime: 30 min). The desired fraction was collected and the organic phasewas evaporated to give a yellow oil. Yield: 6.2 g of2-chloro-α-hydroxy-4-(1-pyrrolidinylmethyl)-benzeneacetic acid(TFA-salt), used as such in the next reaction step (52.5%; TFA-salt).

Final Compounds Class C Preparation of Compound 152

A mixture of 2-chloro-α-hydroxy-4-(1-pyrrolidinylmethyl)-benzeneaceticacid (1.1 g, 2.87 mmol),4-(1-piperazinyl)-N-[3-(1-pyrrolidinyl)phenyl]-benzamide .HCl (1.1 g,2.87 mmol), EDCI (0.55 g, 2.87 mmol), HOBT (0.39 g, 2.87 mmol) and Et₃N(1.6 ml, 11.48 mmol) in DCM (50 ml) was stiffed overnight at r.t. Waterwas added to the mixture, and the organic layer was separated. Theaqueous layer was extracted with DCM (3×30 ml). The combined organiclayer was washed with brine, dried (MgSO₄), filtered and the solvent wasevaporated in vacuo. The residue was purified by flash columnchromatography over silica gel (eluent: DCM/MeOH 30/1). The productfractions were collected and the solvent was evaporated. Yield: 0.8 g ofcrude compound 152 (purity 82% on LCMS). The crude compound 152 waspurified by neutral high performance liquid chromatography (Column:Daisopak 250×20 mm; Mobile Phase: 80-100% CH₃CN in water; Flow Rate: 14ml/min; Finished Time: 15 min). The desired fraction was collected andevaporated in vacuo. Yield: 0.4 g of compound 152 (23%).

Compound 151 was prepared by analogy to compound 152, but2-chloro-4-(1-pyrrolidinylmethyl)-benzeneacetic acid (for which thesynthesis protocol is described in detail in the experimental proceduresfor the Class D compounds) was used as starting material.

Compounds 147, 148, 149 and 150 were also prepared by analogy tocompound 152, starting from the appropriate starting materials.

Experimental Procedures for the Class D Compounds

The experimental procedures for the preparation of the compounds ofClass D, are described in WO2008/148868, the content of which isenclosed by reference in the present application.

In addition, some typical examples of Class D compounds are describedbelow.

Intermediates Class D Preparation of 1-[[3-chloro-4-(2,2-dibromoethenyl)phenyl]methyl]-pyrrolidine

A mixture of 2-chloro-4-(1-pyrrolidinylmethyl)-benzaldehyde (preparedaccording to the teachings in WO2008/148868) (10.0 g, 44.70 mmol) andtetrabromomethane (22.2 g, 67.05 mmol) in DCM (300 ml) was stirred at 0°C. A solution of triphenylphosphine (35.2 g, 134.10 mmol) in DCM (500ml) was added. The mixture was stiffed for 30 min at 0° C. The mixturewas concentrated in vacuo. The residue was taken up into CHCl₃, and theprecipitate was filtered off. The filtrate was concentrated in vacuo.The residue (crude1-[[3-chloro-4-(2,2-dibromoethenyl)phenyl]methyl]-pyrrolidine) was usedas such in the next reaction step.

Preparation of1-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-pyrrolidine

A mixture of pyrrolidine (150 ml) and water (15 ml) was stirred at r.t.1-[[3-chloro-4-(2,2-dibromoethenyl)phenyl]methyl]-pyrrolidine (crude,max. 44.70 mmol) was added to the mixture and subsequently, the mixturewas stirred overnight at r.t. The solvent was evaporated, yielding1-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-pyrrolidine as acrude that was used as such in the next reaction step.

Preparation of 2-chloro-4-(1-pyrrolidinylmethyl)-benzeneacetic acid

A solution of1-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-pyrrolidine (crude,max. 44.70 mmol) in dioxane (100 ml) was stirred at r.t. A 6 M HClsolution was added. The mixture was stirred and refluxed for 3 days. Themixture was concentrated in vacuo. The residue was taken up in water andthe mixture was brought to pH 10 with a 4 N NaOH solution. The solutionwas washed with diethyl ether (3×40 ml). The aqueous layer was acidifiedto pH 3 with a 6 N HCl solution. The mixture was concentrated in vacuo.The residue was purified by neutral high performance liquidchromatography (Column: Lana 300×50 mm, 10 μm; Mobile Phase: 0-20% CH₃CNin water; Flow Rate: 80 ml/min; Finished Time: 25 min). The desiredfraction was collected and evaporated in vacuo. Yield: 2.8 g of2-chloro-4-(1-pyrrolidinylmethyl)-benzeneacetic acid (25% yield overlast 3 steps).

2,6-Dichloro-4-(1-pyrrolidinylmethyl)-benzeneacetyl chloride .HCl wasprepared by analogy to 2-chloro-4-(1-pyrrolidinylmethyl)-benzeneaceticacid by using the appropriate reaction conditions well known to thoseskilled in the art.

2,6-Dichloro-4-(1-pyrrolidinylmethyl)-benzeneacetic acid .HCl wasprepared by analogy to 2-chloro-4-(1-pyrrolidinylmethyl)-benzeneaceticacid by using the appropriate reaction conditions well known to thoseskilled in the art.

Preparation of4-[4-[[[(3,5-dimethoxyphenyl)methyl]amino]carbonyl]phenyl]-1-piperazinecarboxylicacid, 1,1-dimethylethyl ester

A mixture of 3,5-dimethoxybenzenemethanamine (3.34 g, 20 mmol),4-(4-carboxyphenyl)-1-piperazinecarboxylic acid, 1-(1,1-dimethylethyl)ester (6.13 g, 20 mmol), EDCI (4.2 g, 22 mmol), HOBT (2.97 g, 22 mmol),N(CH₂CH₃)₃ (12 ml) and DCM (80 ml) was stirred overnight at r.t. Thesolvent was evaporated. The residue was purified by columnchromatography (eluent: petroleum ether/EtOAc 2/1). The desiredfractions were collected and the solvent was evaporated. Yield: 5.3 g of4-[4-[[[(3,5-dimethoxyphenyl)methyl]amino]carbonyl]phenyl]-1-piperazinecarboxylicacid, 1,1-dimethylethyl ester (58.24% yield).

Preparation ofN-[(3,5-dimethoxyphenyl)methyl]-4-(1-piperazinyl)-benzamide (HCl-salt)

4-[4-[[[(3,5-dimethoxyphenyl)methyl]amino]carbonyl]phenyl]-1-piperazinecarboxylicacid, 1,1-dimethylethyl ester (5.2 g, 11.4 mmol) was dissolved inHCl/dioxane (100 ml) and the reaction solution was stirred overnight.The solvent was evaporated. The solid residue was washed with petroleumether and dried. Yield: 4.2 g ofN-[(3,5-dimethoxyphenyl)methyl]-4-(1-piperazinyl)-benzamide (HCl-salt)as a crude (97.7%). 1 g of the crude product was purified by preparativeHPLC (YMC: 250×80 mm; Mobile Phase: 10-35% CH₃CN % in H₂O (0.1% TFA);Finished Time: 25 min). The desired fractions were collected and solventwas evaporated. The residue was neutralized with an aqueous NaHCO₃solution and extracted with EtOAc. The separated organic layer waswashed with brine, dried (Na₂SO₄), filtered and the solvent wasevaporated to yield a white solid. Yield: 0.4 g ofN-[(3,5-dimethoxyphenyl)methyl]-4-(1-piperazinyl)-benzamide (HCl-salt).

Final Compounds Class D Preparation of Compound 353

A mixture of 2-chloro-4-(1-pyrrolidinylmethyl)-benzeneacetic acid (0.94g, 3.70 mmol) andN-[(3,5-dimethoxyphenyl)methyl]-4-(1-piperazinyl)-benzamide (HCl-salt)(1.5 g, 3.83 mmol) in DCM (20 ml) was stirred at r.t. Et₃N (1.3 ml, 9.58mmol) was added to the mixture. Then EDCI (0.73 g, 3.83 mmol) and HOBT(0.52 g, 3.83 mmol) were added to the mixture. The mixture was stirredovernight at r.t. The mixture was washed with water, dried (MgSO₄),filtered and the solvent was evaporated in vacuo. The residue waspurified by flash column chromatography over silica gel (eluent:CH₂Cl₂/CH₃OH 20/1). The product fractions were collected and the solventwas evaporated. Yield: 0.78 g of compound 353 (36%).

Preparation of Compound 358

A mixture of 2,6-dichloro-4-(1-pyrrolidinylmethyl)-benzeneacetylchloride. HCl and 2,6-dichloro-4-(1-pyrrolidinylmethyl)-benzeneaceticacid. HCl (1.29 g of the mixture) was added portionwise to a stiffingmixture of N-[(3,5-dimethoxyphenyl)methyl]-4-(1-piperazinyl)-benzamide.HCl (1.406 g, 0.00358 mol) and NaHCO₃ (0.993 g, 0.0118 mol) in CH₃CN (60ml; dried on molecular sieves). The r.m. was stirred under N₂ atmospherefor 4 h. Subsequently, Et₃N (1 ml) and HBTU (1.358 g, 0.00358 mol) wereadded and the r.m. was stirred at r.t. for 65 h. Then, the mixture waspoured into stirring H₂O (300 ml) and this aqueous mixture was stirredfor 20 min. The product was filtered off and washed with H₂O (3×). Theproduct was stirred in boiling 2-propanol (70 ml), filtered off hot, andthe filtrate was left standing for 3 h (crystallization started after 5min). The product was filtered off, washed with 2-propanol (3×), anddried (50° C., in vacuo) to yield 1.12 g of compound 358 (50%). Anadditional amount of compound 358 (0.481 g) was obtained by evaporationof the filtrate and purification of the residue by HPLC. The desiredfractions were evaporated and crystallized from boiling 2-propanolagain.

Compounds 354, 355, 359, 360, 361, 362, 363 and 364 from Class D wereprepared by analogy to compound 353, starting from the appropriatestarting materials.

Compounds 356 and 357 from Class D were prepared by analogy to compounds152 from Class C, starting from the appropriate starting materials.

The tables below list compounds of class A, class B, class C or class D.The novel compounds of group Q (compounds 147 till 152 from Class C andcompounds 353 till 364 from Class D) are enclosed in class C and classD.

Table for the Class A Compounds

TABLE A1

Compound 8 

Compound 10

Compound 11

Compound 12

Compound 13

Compound 14

Compound 15

Compound 16

Compound 17

Compound 18

Compound 19Tables for the Class B Compounds

TABLE B1

Co. No. A X R¹ R^(q)  1 N

 2 N

 3 N

 4 N

 5 N

 6 N

 7 CH

 8 N

 9 N

10 N

11 N

12 N

13 N

14 N

15 N

16 N

17 N

18 N

19 N

20 N

21 N

22 N

23 N

24 N

25 N

26 N

27 N

28 N

29 N

30 N

31 N

32 N

33 N

34 N

35 N

36 N

37 N

38 N

39 N

40 N

41 N

42 N

43 N

44 CH

45 N

46 CH

47 N

48 CH

49 N

50 CH

51 N

52 N

53 N

54 N

55 N

56 N

57 N

58 N

59 N

60 N

61 N

62 N

63 N

64 N

65 N

TABLE B2

Co. No. X R¹ R² Salt 66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

trifluoroacetate salt 116

117

Tables for the Class C Compounds

TABLE C1

Comp. no. R^(1a) R^(1b) R^(1c) 125 H

H 12 H

H 13 H

H 4

H H 14 H

H 15 H H

16 H

H 17 H

H 18

H H 19 H H

20 H

H 21 H H

22

H H 23 H

H 24 H H

25 H H

26

H H 27 H H

28 H

H 29 H H

30 H H

31 H

H 32

H H 33 H H

34

H H 35

H H 36 H

H 127 H

H 37 H

H 38 H H

39

H H 40 H

H 41 H

H 42

H H 43 H

H 44 H H

45

H H 126 H H

TABLE C2

Comp. no. A R¹ Salt 46 CH

tri- fluoro- acetate 47 CH

tri- fluoro- acetate 48 CH

tri- fluoro- acetate 10 CH

tri- fluoro- acetate 49 CH

tri- fluoro- acetate 1 CH

50 CH

51 CH

52 CH

3 CH

53 CH

54 CH

55 CH

56 CH

57 CH

58 CH

59 CH

60 CH

61 CH

62 CH

63 CH

64 CH

11 N

2 N

65 N

66 N

67 N

TABLE C3

Co. no. X R²  6 —C═O

 68 —NH—C═S

 8 —NH—C═S

 69 —NH—C═O (CH₃)₃—C—  5 —NH—C═O

 70 —NH—C═O

 71 —NH—C═O

 72 —NH—C═O

 73 —NH—C═O

 74 —NH—C═O

 75 —NH—C═O

 76 —NH—C═O

 77 —NH—C═O

 78 —NH—C═O

 79 —NH—C═O

 80 —NH—C═O

 81 —NH—C═O

 82 —NH—C═O

 83 —NH—C═O

 84 —NH—C═O

 85 —NH—C═O

 86 —NH—C═O

 87 —NH—C═O

 88 —NH—C═O

 89 —NH—C═O

 90 —NH—C═O

 91 —NH—C═O

 92 —NH—C═O

 93 —NH—C═O

 94 —NH—C═O

 9 —NH—C═O

 95 —NH—C═O

 96 —NH—C═O

 97 —NH—C═O

 98 —NH—C═O

 99 —NH—C═O

100 —NH—C═O

101 —NH—C═O

102 —NH—C═O

103 —NH—C═O

104 —NH—C═O

105 —NH—C═O

106 —NH—C═O

TABLE C4

Co. no. R² 107 CH₂═CH—CH₂—  7

108

109

110

111

128

112

113

114

115

116

117

118

TABLE C5

Co. no. R² 119 CH₃—CH₂—CH₂— 120

121

122

123

124

TABLE C6

Comp. no. X R² R^(1a) R^(1a′) R^(1b) R^(1c) R⁷ 131 —CH₂—C═O

H H

H H 134 —CH₂—C═O

Cl Cl H H H 135 —CH₂—NH—C═O

Cl Cl H H H 133 —NH—C═O

H H H —OCH₃ F 130 —NH—C═O

H H

H H 147 —CH₂—C═O

H H

H H 148 —CH₂—C═O

H H

H H 149 —CH₂—C═O

H H

H H 150 —CH₂—C═O

H H

H H 151 —CH₂—C═O

H H

H H 152 —CH(OH)—C═O

H H

H H 129 —NH—C═O

H H

H H 132 —CH₂—C═O

H H

H H

TABLE C7

Comp. no. X R² R^(1a) R^(1b) R^(1c) 144 —NH—C═O

H H 142 —CH₂—C═O

H Br H 141 —CH₂—C═O

H H —(CH₂)₃CH₃ 139 —O—C═O

H

H 137 —NH—C═O

H

H 146 —CH₂—C═O

H

H 145 —CH₂—C═O

H

H 140 —NH—C═O

H

H 143 —NH—C═O

H

H 138 —NH—C═O

H

H 136 —NH—C═O

H

HTables for the Class D Compounds

TABLE D1

^(R)*, ^(S)* = relative stereochemistryAnalytical Part

Analytical Data for the Compounds of Group Q (Compounds 147-152 fromClass C And Compounds 353-364 from Class D):

LCMS

For (LC)MS-characterization of the compounds of the present invention,the following methods were used.

General Procedure A

The LCMS analyses for a number of compounds were done at the SurveyorMSQ™ (Thermo Finnigan, USA) comprising a photo diode array detector(PDA; 190-800 nm) and a column as specified in the respective methodsbelow. Flow from the column was split to a MS spectrometer. The MSdetector was configured with APCI (atmospheric pressure chemicalionization, + or − ions). Mass spectra were acquired by scanning from 45to 1000 (of atomic mass unit) in 0.3 seconds. Typical APCI conditionsuse a corona discharge current of 10 μA and a cone voltage of 30 V. TheAPCI probe temperature was 640° C. Nitrogen was used as the nebulizergas. Data acquisition was performed with an Xcalibur™ data system.

General Procedure B

The HPLC measurement was performed using an Agilent 1100 modulecomprising a pump, a diode-array detector (DAD) (wavelength used 220nm), a column heater and a column as specified in the respective methodsbelow. Flow from the column was split to a Agilent MSD Series G1946C andG1956A. MS detector was configured with API-ES (atmospheric pressureelectrospray ionization). Mass spectra were acquired by scanning from100 to 1000. The capillary needle voltage was 2500 V for positiveionization mode and 3000 V for negative ionization mode. Fragmentationvoltage was 50V. Drying gas temperature was maintained at 350° C. at aflow of 10 l/min

Method 1

In addition to general procedure A: Reversed phase HPLC was carried outon a Waters XTerra MS C18 column (3.5 μm, 2.1×30 mm) with a flow rate of1.0 ml/min Two mobile phases (mobile phase A: 0.1% aqueous solution offormic acid; mobile phase B: CH₃CN) were used. First, 100% A was holdfor 0.1 minutes (min). Then a gradient was applied to 5% A and 95% B in3 min and hold for 0.8 min. The injection volume was 1 μl. The columnwas at room temperature.

Method 2

In addition to general procedure B: Reversed phase HPLC was carried outon a YMC-Pack ODS-AQ, 50×2.0 mm 5 μm column with a flow rate of 0.8ml/min. Two mobile phases (mobile phase A: water with 0.1% TFA; mobilephase B: CH₃CN with 0.05% TFA) were used. First, 90% A and 10% B washold for 0.8 min. Then a gradient was applied to 20% A and 80% B in 3.7min and hold for 3 min. Typical injection volumes of 2 μl were used.Oven temperature was 50° C. (MS polarity: positive)

Method 3

In addition to general procedure B: Reversed phase HPLC was carried outon an Ultimate XB-C18, 50×2.1 mm 5 μm column with a flow rate of 0.8ml/min Two mobile phases (mobile phase C: 10 mmol/L NH₄HCO₃; mobilephase D: CH₃CN) were used. First, 90% C and 10% D was hold for 0.8 min.Then a gradient was applied to 20% C and 80% D in 3.7 min and hold for 3min. Typical injection volumes of 2 μl were used. Oven temperature was50° C. (MS polarity: positive)

Method 4

In addition to general procedure B: Reversed phase HPLC was carried outon an Ultimate XB-C18, 50×2.1 mm 5 μm column with a flow rate of 0.8ml/min Two mobile phases (mobile phase C: 10 mmol/L NH₄HCO₃; mobilephase D: CH₃CN) were used. First, 100% C was hold for 1 min. Then agradient was applied to 40% C and 60% D in 4 min and hold for 2.5 min.Typical injection volumes of 2 μl were used. Oven temperature was 50° C.(MS polarity: positive)

Melting Points

For a number of compounds (147-150 of Class C; 358-364 of Class D), m.p.were determined by using a Gallenkamp apparatus from Sanyo Gallenkamp.For a number of compounds (151-152 of Class C; 353-357 of Class D), m.p.were determined with a WRS-2A melting point apparatus that was purchasedfrom Shanghai Precision and Scientific Instrument Co. Ltd. Meltingpoints were measured with a linear heating up rate of 0.2-5.0° C./min.The reported values are melt ranges. The maximum temperature was 300° C.

TABLE Y (LC)MS analytical data and m.p. - R_(t) means retention time (inminutes); [MH]⁺ means the protonated mass of the compound (free base);Method refers to the method used for (LC)MS; ‘dec.’ means decomposition.Comp. Nr. R_(t) [MH]⁺ Method m.p. (° C.) 147 - Class C 1.62 620 1262-263 148 - Class C 1.60 663 1 180-182 149 - Class C 1.63 677 1250-252 150 - Class C 1.68 713 1 240-242 151 - Class C 3.41 586 2224.1-225.4 152 - Class C 4.84 602 3 138.7-140.9 353 - Class D 3.49 5912 126.6-128.1 354 - Class D 3.23 600 2 206.3-209.4 355 - Class D 3.42561 2 153.3-155.2 356 - Class D 3.10 616 2 134.4-137.0 357 - Class D5.65 607 4 dec. at 124.8 358 - Class D 1.57 625 1 199-200 359 - Class D1.61 677 1 240-241 360 - Class D 1.52 668 1 159-160 361 - Class D 1.53691 1 164-166 362 - Class D 1.51 682 1 123-126 363 - Class D 1.61 727 1241-243 364 - Class D 1.56 718 1 152-154

Analytical data for the other Class A, Class B, Class C and Class Dcompounds are listed in WO2008/148851, WO2008/148840, WO2008/148849 andWO2008/148868, the contents of which are enclosed by reference in thepresent application.

Pharmacological Example

All mpk (mg/kg/day) values mentioned in the measurements describedbelow, were estimated based on average food intake and average bodyweight.

A) Measurement of Inhibition of DGAT1 Activity by the Compounds of ClassA, Class B, Class C and Class D

The inhibiting activity of compounds of Class A, Class B, Class C andClass D on DGAT1 activity was screened in a single well procedure assayusing DGAT1 comprising membrane preparations and DGAT1 substratecomprising micelles and determining formed radio-active triacylglycerolcoming in close proximity of a flashplate surface by radioluminescence.

Said assay is described in full detail in WO2006/067071, the content ofwhich is incorporated herein by reference.

By DGAT1 activity is meant the transfer of coenzyme A activated fattyacids to the 3-position of 1,2-diacylglycerols, thus forming atriglyceride molecule, by enzyme DGAT1.

Step 1 of the Assay: Expression of DGAT1

human DGAT1 (NM012079.2) was cloned into the pFastBac vector, containingtranslation start, a FLAG-tag at the N-terminus as described inliterature and a viral Kozak sequence (AAX) preceding the ATG to improveexpression in insect cells. Expression was done as described inliterature (Cases, S., Smith, S. J., Zheng, Y., Myers H. M., Lear, S.R., Sande, E., Novak, S., Collins, C., Welch, C. B., Lusis, A. J.,Erickson, S. K. and Farese, R. V. (1998) Proc. Natl. Acad. Sci. USA 95,13018-13023.) using SF9 cells.

Step 2 of the Assay: Preparation of DGAT1 Membranes

72h transfected SF9 cells were collected by centrifugation (13000 rpm-15min-4° C.) and lysed in 2×500 ml lysisbuffer (0.1M Sucrose, 50 mM KCl,40 mM KH₂PO₄, 30 mM EDTA pH 7.2. Cells were homogenized by celldisruptor. After centrifugation 1380 rpm-15 min-4° C. (SN discarded),pellet was resuspended in 500 ml lysisbuffer and total cell membranescollected by ultracentrifugation at 34000 rpm(100 000 g) for 60 min (4°C.). The collected membranes were resuspended in lysis buffer, dividedin aliquots and stored with 10% glycerol at −80° C. until use.

Step 3 of the Assay: Preparation of DGAT Substrate Comprising Micelles

Materials

-   a) 1,2-dioleoyl-sn-glycerol, 10 mg/ml (1,2-diacylglycerol (DAG))    Dissolve in acetonitrile; evaporate the acetonitrile solution under    nitrogen and reconstitute in chloroform at a final concentration of    10 mg/ml.-   b) L-α-phosphatidylcholine, 1 mg/ml (phosphatidylcholine (PC))    -   Dissolve in chloroform at a final concentration of 1 mg/ml and        store at 4° C.-   c) L-α-phosphatidyl-L-serine, 1 mg/ml (phophatidylserine (PS))    -   Dissolve in chloroform at a final concentration of 1 mg/ml and        store at 4° C.        Method

Add 1 ml dioleoyl-sn-glycerol (10 mg/ml) to 10 ml ofL-α-phosphatidylcholine (1 mg/ml) and 10 ml of L-α-phosphatidyl-L-serine(1 mg/ml) in a thick glass recipient. Evaporate under nitrogen and puton ice for 15 min Reconstitute in 10 ml Tris/HCl (10 mM, pH 7.4) bysonication on ice. The sonification process includes sonification cyclesof 10 seconds in the sonification bath followed by 10 seconds cool downon ice and repeating this sonification cycle till a homogeneous solutionis obtained (takes about 15 min). The thus obtained micelles are storedat −20° C. till later use and contain DAG at a final concentration of1.61 mM.

Step 4 of the Assay: DGAT FlashPlate™ Assay

Materials

-   a) Assaybuffer-   50 mM Tris-HCl (pH 7.4), 150 mM MgCl₂, 1 mM EDTA, 0.2% BSA.-   b) N-ethylmaleimide, 5M    -   Dissolve 5 g into a final volume of 8 ml DMSO 100% and store at        −20° C. in aliquots till later use.-   c) Substrate mix (for 1 384 well plate=3840 μl)-   612 μl micelles stock (51 μM final)-   16.6 μl oleoylCoA 9.7 mM-   23 μl [³H]-oleoylCoA (49 Ci/mmol, 500 μCi/ml)-   3188.4 μl Tris pH 7.4, 10 mM-   d) Enzyme mix (for 1 384 well plate=3520 μl) (5 μg/ml)    -   Add 11.73 μl of DGAT membrane stock (1500 μg/ml stock) to 3508        μl assay buffer.-   e) Stop mix (for 1 384 well plate=7.68 ml) (250 mM)    -   Add 384 μl of N-ethylmaleimide (5M) to 3.456 ml DMSO 100%, and        further dilute 3.84 ml of said solution with 3.84 ml DMSO 10%.        Method

DGAT activity in membrane preparations was assayed in 50 mM Tris-HCl (pH7.4), 150 mM MgCl₂, 1 mM EDTA and 0.2% BSA, containing 50 μM DAG, 32μg/ml PC/PS and 8.4 μM [³H]-oleoylCoA (at a specific activity of 30nCi/well) in a final volume of 50 μl in 384-well format using the redshifted Basic Image FlashPlate™ (Perkin Elmer Cat.No. SMP400).

In detail, 10 μl enzyme mix and 10 μl substrate mix were added to 30 μlof assay buffer, optionally in the presence of 1 μl DMSO (blank andcontrols) or 1 μl of the compound to be tested. This r.m. was incubatedfor 120 min at 37° C. and the enzymatic reaction stopped by adding 20 μlof the stop mix. The plates were sealed and the vesicles allowed tosettle overnight at room temperature. Plates were centrifuged for 5 minat 1500 rpm and measured in Leadseeker.

Experiments with different concentrations of the test compound wereperformed and curves were calculated and drawn based on % CTRL_(min) (%of normalized control). % CTRL_(min) was calculated according toequation 1,%CTRL_(min)=(sample−LC)/(HC−LC)  Equation 1:where HC (high control) refers to the median of radioluminescence valuemeasured in the wells with enzyme and substrate but without testcompound, LC (low control) refers to median background radioluminescencevalue measured in the wells with substrate without enzyme and withouttest compound, and sample refers to the radioluminescence value measuredin the wells with substrate, enzyme and test compound at a particularconcentration.

The calculated % CTRL_(min) values form a sigmoidal dose responsedescending curve and from this curve pIC₅₀ values were calculated(−logIC₅₀ where IC₅₀ represents the concentration at which the testcompound gives 50% inhibition of DGAT1 activity). All the testedcompounds of Class A, C and D showed pIC₅₀ values between 5 and 9. Allthe tested compounds of Class B showed pIC₅₀ values between 5 and 8.5.

In order to determine selectivity of the present compounds for DGAT1compared to DGAT2, the inhibiting activity of the compounds on DGAT2 wasalso determined in the above assay, slightly modified to obtain optimalassay conditions for DGAT2. The tested compounds did not show inhibitingactivity for DGAT2 (Human DGAT2 (NM032564) was cloned and expressed asdescribed in J. Biolog. Chem. 276(42), pp 38870-38876 (2001)).

For a selected number of compounds, the pIC50 values are shown in TableE.

TABLE E pIC₅₀ values Co. Nr. pIC₅₀ Co. Nr. pIC₅₀ Co. Nr. pIC₅₀ 151- 6.50354- 6.19 361- 7.87 Class C Class D Class D 152- 7.45 355- 6.04 362-8.04 Class C Class D Class D 147- 7.41 356- 7.13 363- 7.94 Class C ClassD Class D 148- 8.04 357- 7.26 364- 8.24 Class C Class D Class D 149-8.21 358- 7.59 352- 6.45 Class C Class D Class D 150- 8.22 359- 7.55351- 6.62 Class C Class D Class D 353- 6.59 360- 8.12 267- 6.97 Class DClass D Class D

Pharmacological data for the other Class A, Class B, Class C and Class Dcompounds are listed in WO2008/148851, WO2008/148840, WO2008/148849 andWO2008/148868, the contents of which are enclosed by reference in thepresent application.

B) In Vivo Study for Effect of Test Compound on GLP-1 Plasma Levels

Elevation of GLP-1 plasma levels by a DGAT inhibitor can be studied asfollows:

Dogs are deprived from food for a period of 22 h. At time 0, animals aregiven a liquid meal, containing 18% fat (w/w), by gavage with a stomachtube. The test compound is given orally together with the meal.Afterwards, a postprandial plasma profile is determined for GLP-1.Therefore, blood is collected at predetermined time intervals inice-cooled Vacutainers EDTA-plasma tubes and GLP-1 levels are measuredin the samples taken at 0 h (just before the meal) and at 0.5, 1, 2, 4,6, 8 and 24 h after dosing. Six dogs (3 males and 3 females) areincluded per dosage group and the plasma GLP-1 profile is compared withtheir own GLP-1 profile previously determined in the same conditions butwithout administration of the test compound. GLP-1 determinations inplasma are performed with a Glucagon-like peptide-1 (active) ELISA kit96-well plate of LINCO Research.

C) Food Intake/Body Weight Effect of DGAT/Fenofibrate Combination

General Procedure

Male C57BL/6 mice were housed in individually ventilated cages undercontrolled temperature (21° C.), humidity (45-65%) and light (12 h-12 hreverse light/dark cycle; Lights on—6 PM-6 AM). Mice were set on 60 kcal% fat energy diet until their average body weight was over 45 grams, atwhich time they were switched to a 45 kcal % fat diet.

For the purpose of Tests A, B and C, the mice were moved into modifiedtype-2 cages with: doublewide food cup, wire grids and a tissue forbedding for several months before experiment to adapt to newhousing/feeding conditions. Food (Research diets 45 kcal % dietD12451—see Scheme A) was provided in powdered form in a food hopperlocated off the front of the cage. Mice had been used to test severalcompounds for effects on food intake before being used in the currentexperiment, but had a wash-out period of at least one month beforestarting the current experiments.

Scheme A: Composition of control diet (high- fat) and premix (used foradding drug) Control Diet Added during D12451 Premix diet preparationIngredient g/kg diet D04071407px g/kg diet Casein, 80 Mesh 233.1 233.1L-Cystine 3.5 3.5 Corn Starch 84.8 84.8 Maltodextrin 10 3.5 3.5 Sucrose201.4 201.4 Cellulose 58.3 58.3 Soybean Oil 29.1 29.1 Lard 206.8 104.9102 Mineral Mix S10026 11.7 11.7 DiCalcium Phosphate 15.1 15.1 CalciumCarbonate 6.4 6.4 Potassium Citrate, 1 H20 19.2 19.2 Vitamin Mix 11.711.7 Choline Bitartrate 2.3 2.3 FD&C Red Dye #40 0.1

Compound 223 of Class D (Tests A and B) or compound 358 (Test C) ofClass D, and/or fenofibrate (also called ‘F’ in the continuation of thepharmacological examples) were brought to a fine emulsion by stiffing inthe appropriate amount of soybean oil for 1 day. This was then mixedwith the diet premix (Scheme A). The diet premix was formulated tocontain none of the necessary soybean oil, and only half the finalamount of lard. The soybean oil, and the rest of the lard was addedin-house during diet preparation. After the soybean oil/drug was mixedwith the premix for 15 min, the remainder of the lard was added tocomplete the diet. Diet was provided in powder form.

The mice were weighted the day before trial onset. For treatmentallocation, mice were ranked according to body weight and randomlyassigned to treatments within repetitions/blocks (40 mice, 4 treatments,10 repetitions/block, unless otherwise mentioned). The food intake theday before trial onset was also measured.

At trial onset, mice's food (diet D12451) was replaced with the‘inhouse’ diet made from premix D04071407px and added oil/lard,fenofibrate and/or the DGAT inhibitor. In tests A and B compound 223 ofClass D (also called ‘D’ in the continuation of the pharmacologicalexamples) was used:

Food cups were filled and weighted daily during the experiment. Bodyweight was recorded every 2^(nd) or 3^(rd) day.

Food Intake and Body Weight data were analyzed using General LinearModels procedures appropriate for a 2×2 factorial design with blockingand repeated measures. Means comparisons were done using Duncan'sMultiple Range test (SAS For Windows, Version 8.02; SAS®, Cary, N.C.).Results were expressed as means±SEM (standard error of the mean).

Test A

In test A, the efficacy of the treatment in DIO C57BL/6 mice with onlyfenofibrate and only a DGAT inhibitor (compound 223 from Class D) wascompared with the combined treatment with both D and fenofibrate.

For the purpose of test A, the mice were assigned to one of thefollowing treatments:

-   -   45 kcal % fat diet (Control)    -   45 kcal % fat diet+0.05% fenofibrate (F)    -   45 kcal % fat diet+0.04% compound 223 from Class D (D)    -   45 kcal % fat diet+0.04% compound 223 from Class D+0.05%        fenofibrate (D+F)

The results of test A are shown in FIGS. A1 and A2.

In FIG. A1 it can be seen that except for 1 or 2 days out of the 12 daytrial, food intake of mice fed with the compound 223 of Class D (D) orfenofibrate-containing (F) diet was not significantly less than controlmice. In contrast, food intake of mice fed with the compound 223 ofClass D and fenofibrate-containing (D+F) diet was significantly less(P<0.05) on 9 out of 12 days. The cumulative food intake of the compound223 of Class D group (D) and the fenofibrate group (F) was notsignificantly less than the control group when compared by DuncansMultiple Range test (3.2% and 7.5% respectively); whereas food intake ofthe group with the compound 223 of Class D and fenofibrate-containing(D+F) diet was significantly less (23%) than all other groups (P<0.05).When cumulative intake was analysed as a 2×2 factorial design, there wasa significant DGAT effect and fenofibrate effect (P<0.005), but therewas also a significant DGAT (compound 223 from Class D)×fenofibrateinteraction, indicating that the combined effect was larger than themain effect of either alone (P<0.05) (synergistic effect).

The average daily drug intake of mice fed with the compound 223 of ClassD or fenofibrate-containing diet was 23.5 and 29 mpk/d respectively. Theaverage daily drug intake of mice fed the compound 223 of Class D andfenofibrate-combination diet was 43.2 mg/kg/day.

In FIG. A2 it can be seen that by day 2, body weight loss of mice fedwith the compound 223 of Class D and fenofibrate-containing diet wassignificantly greater than control mice (P<0.05). By day 4, body weightchange of all drug treated mice was significantly different thancontrols. Mice fed with the compound 223 of Class D orfenofibrate-containing diet lost from 1-2 grams during the trial,whereas controls gained 0.6 grams. In contrast, mice fed with thecompound 223 of Class D and fenofibrate-combination diet (D+F)significantly lost more weight than mice fed with either drug alone,indicating a synergistic effect of the 2 compounds on weight loss. Whenday 12 weight loss was analysed by a 2×2 factorial design, the maineffect of DGAT and fenofibrate were both significant (P<0.001), butDGAT×fenofibrate interaction was also significant (type 3 SS, P<0.05).This test supports the increased effect on weight loss of thecombination diet when compared with single treatment.

At the end of test A, blood was collected under isoflurane anesthesiafor serum biochemistry determinations. There was no indication ofenhanced liver enzymes with the combination diet. Blood glucose andserum triglyceride levels were consistently lower in the (D+F) dietgroup than the control group.

Test B

In test B, the efficacy of the treatment in DIO C57BL/6 mice with thefenofibrate/compound 223 from Class D combination was compared atdifferent doses. In test A, fenofibrate and compound 223 of Class D wereincluded at 0.05 and 0.04% of the diet (w/w) respectively. In test B,fenofibrate (F)/compound 223 of Class D (D) was included at 3 lowerdoses—0.05 F/0.02 D, 0.025 F/0.02 D and 0.0125 F/0.01 D.

For the purpose of test B, the mice were assigned to one of thefollowing treatments:

45 kcal % fat diet (Control)

45 kcal % fat diet+0.02% D+0.05% F (0.05 F/0.02 D)

45 kcal % fat diet+0.02% D+0.025% F (0.025 F/0.02 D)

45 kcal % fat diet+0.01% D+0.0125% F (0.0125 F/0.01 D)

The results of test B are shown in FIGS. B1, B2 and B3.

The average daily drug intake of F/D was 26.0/10.4, 13.2/10.6 and6.6/5.3 mpk/d respectively for mice fed with the high, medium and lowconcentration diets. In FIG. B1, it can be seen that the baseline foodintake (i.e. day 0) of mice fed the 0.0125/0.01 was significantly lowerthan for other groups. During the first day of exposure to thedrug-containing diets, all treatment groups ate significantly less thancontrols. (2.6 vs. 3.7 g for treated vs. controls respectively). Treatedmice ate significantly (P<0.05 or less) less than controls on all trialdays except days 9, 14 and 15.

In FIG. B2, it can be seen that body weight change of mice fed withF/D-containing diets was significantly different from control mice bythe 2^(nd) day of the trial (all P<0.001). Body weight changedsignificantly over time (time effect, P<0.001), and was significantlyinfluenced by treatment (time×treatment interaction (P<0.05).

In FIG. B3, food intake of all treatment groups on day 1 is shown. Allgroups ate about 30% less than controls regardless of dietary D/Fcombination.

It can be concluded that compound 223 of Class D in combination withfenofibrate, reduced food intake in diet-induced obese mice for almost 2weeks. This reduction in food intake was accompanied with a significantweight change when compared to controls. Control mice gained almost 2grams during the first 5 days of the experiment. It appeared that micehad lost some weight during adaptation to the feeding cages. Althoughthey regained most of this weight prior to the trial, some control miceclearly still regained weight during the first week of the experiment.This was not the case for mice treated with the combination of compound223 of Class D and fenofibrate, even when the 2 were combined in thediet at 0.01 and 0.0125% w/w respectively. These results suggest thatfenofibrates may reduce the efficacious dose of a DGAT inhibitor andprolong the time a DGAT inhibitor will reduce food intake.

Test C

In test C, the efficacies of the treatments in DIO C57BL/6 mice withonly fenofibrate and only a DGAT inhibitor (compound 358 from Class D)were compared with the combined treatment with both compound 358 ofClass D and fenofibrate.

For the purpose of test C, the 32 DIO mice (n=8/group, average startingweight 46.5 g) were assigned to one of the following treatments:

45 kcal % fat diet (Control)

45 kcal % fat diet+0.05% fenofibrate (F)

45 kcal % fat diet+0.04% compound 358 from Class D

45 kcal % fat diet+0.04% compound 358 from Class D+0.05% fenofibrate (F)

The results of test C are shown in FIGS. C1 and C2.

In FIG. C1 it can be seen that food intake of mice fed with a dietcontaining only compound 358 of Class D or a diet only containingfenofibrate, was not significantly less than control mice. Food intakeof mice fed with the compound 358 of Class D+fenofibrate-containing dietwas only significantly less (P<0.05) from controls on days 1 to 3, dueto an increase in food intake above baseline levels in control micerather than a decrease in intake of compound 358+ fenofibrate-treatedmice. The 21-day cumulative food intake of all drug-treated mice turnedout not to be significantly less than the control group, although therewas a tendency for mice fed compound 358 of Class D andfenofibrate-containing diet to eat less.

The average daily drug intake of mice fed with the compound 358 of ClassD or fenofibrate-containing diet was 27 and 34 mpk/d respectively. Theaverage daily drug intake of mice fed the compound 358 of Class D andfenofibrate-combination diet was 58 mg/kg/day.

When analysed as a 2×2 factorial experiment (FIG. C2), both DGAT andfenofibrate treated mice gained less weight than controls (21 days bodyweight change, both main effects P<0.05). The combination of the 2treatments resulted in a weight loss corresponding to the additiveeffect of both (interaction P>0.05, no synergistic effect).

D) Short-Term Food Intake Effect of DGAT/Fenofibrate Combination in LeanC57BL/6 mice.

In Test A and Test B, it was demonstrated that DGAT inhibition (compound223 of Class D, also called ‘D’) in combination with fenofibrate (F)significantly reduced food intake and body weight of diet-induced obesemice fed a high-fat diet to a greater degree than when either compoundwas administered alone. To further evaluate the mechanism of action ofthis food intake reduction, it was evaluated whether combined treatmentwith a DGAT inhibitor (compound 223 of Class D) and fenofibrate reducefood intake in mice fed with a low-fat diet.

For the experiment, animals were moved into modified type-2 cages asdescribed before. Once in the feeding cages, mice were adapted to a 10kcal % fat diet for 1 week before trial 1 was started.

For the purpose of this test, the mice were assigned to one of thefollowing treatments:

Low Fat Diets (Trial 1; FIG. D1):

10 kcal % fat diet (Control)

10 kcal % fat diet+0.01% D+0.0125% F (0.01% D/0.0125% F)

10 kcal % fat diet+0.04% D+0.05% F (0.04% D/0.05% F)

High Fat D1et (Trial 2; FIG. D2)

45 kcal % fat diet (Control)

45 kcal % fat diet+0.01% D+0.0125% F (0.01% D/0.0125% F)

45 kcal % fat diet+0.02% D+0.05% F (0.02% D/0.05% F)

Compound 223 of Class D (D) and fenofibrate (F) were brought to a fineemulsion by stirring in the appropriate amount of soybean oil for 1 day.This was then mixed with the diet premix. After the soybean oil/drug wasmixed with the premix for 15 min, the necessary amount of the lard wasadded to complete the diet. Diet was provided in powder form.

Mice's ‘baseline’ (BL) food intake was measured for 1 day before bothTrial 1 (low-fat diet) and 2 (high-fat diet). For treatment allocation,mice were ranked according to their pretrial food intake and randomlyassigned to treatments within repetitions/block (30 mice, 3 treatments,8-9 repetitions/block). Several mice had low or high food intakes andwere not included in the experiment.

Food intake data were analysed using General Linear Models proceduresappropriate for a randomized complete block design. Means comparisonswere done using Duncan's Multiple Range test (SAS For Windows, Version8.02; SAS®, Cary, N.C.). Results are expressed as means±SEM.

Trial 1: Food intake of lean mice fed a low-fat diet

Mice were given 1 week to adapt to the food intake cages and a low-fatpowdered diet (Research Diets D12450B—10 kcal % fat). After 1 day ofbaseline food intake measurement, mice's food was replaced by the same10 kcal % fat diet containing 0/0, 0.01/0.0125 or 0.04/0.05% w/w D/F.The food cups were filled and weight daily during the 3-day experiment.

In FIG. D1 (Trial 1), it can be seen that food intake of mice fed thediet containing a 0.01/0.0125 D/F was not reduced at any time during the3-day trial, whereas mice fed the diet containing 0.04/0.05 D/F reducedtheir food intake by 9% on day 1, but ate similar amounts as controlsthereafter.

The average daily drug intake of F/D was 71/57 or 17/14 mpk/drespectively for mice fed the high, and low concentration diets.

Trial 2: Food intake of lean mice fed a high-fat diet

At the termination of trial 1, mice were switched to a high-fat diet(D12451—45 kcal % fat) and allowed to adapt for 3 days. Once adapted,food intake was recorded for 1 day to establish a baseline food intake(for treatment allotment). The following day, mice were switched to thesame 45 kcal % fat diet containing 0/0, 0.01/0.0125 or 0.02/0.05% w/wD/F (FIG. D2).

In FIG. D2, it is shown that food intake of mice fed the dietscontaining a 0.01/0.0125% and 0.02/0.05% D/F was significantly reducedcompared to controls, especially on day 1. Thereafter lean mice adaptedmore quickly than was generally been observed with obese mice. By day 2,mice were eating ˜90% of control values.

The average daily drug intake of F/D was 44/18 or 10.8/8.6 mpk/drespectively for mice fed the high, and low concentration diets.

It can be seen from FIG. D3 that food intake during the first 24 h ofexposure to the drug-supplemented diet (0.01% D/0.0125% F) wassignificantly reduced in mice fed a high-fat diet (24% below controllevels), but not in mice fed a low-fat diet (4% below control levels).These results clearly indicate that a certain amount of dietary fat isnecessary for the feeding suppressive effects of D/F.

E) Composition examples

“Active ingredient” (a.i.) as used throughout these examples relates to,unless otherwise is indicated,

-   a) a combination of a DGAT inhibitor and a PPAR agonist or a prodrug    thereof; in particular to any one of the exemplified DGAT inhibitors    combined with a fibrate; or-   b) a compound of group Q.

Typical examples of recipes for the formulation of the invention are asfollows:

1. Tablets

Active ingredient 5 to 100 mg Di-calcium phosphate 20 mg Lactose 30 mgTalcum 10 mg Magnesium stearate 5 mg Potato starch ad 200 mg

In addition to tablets wherein both the DGAT inhibitor and the PPARagonist are comprised together in 1 tablet, the DGAT inhibitor and thePPAR agonist may also be present in separate tablets. In that case, theactive ingredient will be the DGAT inhibitor for one tablet and the PPARagonist for the second tablet.

2. Suspension

An aqueous suspension is prepared for oral administration so that eachmilliliter contains 1 to 5 mg of active ingredient, 50 mg of sodiumcarboxymethyl cellulose, 1 mg of sodium benzoate, 500 mg of sorbitol andwater ad 1 ml.

3. Injectable

A parenteral composition is prepared by stirring 1.5% (weight/volume) ofactive ingredient in 0.9% NaCl solution.

4. Ointment

Active ingredient 5 to 1000 mg Stearyl alcohol 3 g Lanoline 5 g Whitepetroleum 15 g Water ad 100 g

The invention claimed is:
 1. A combination of a PPAR-α agonist or aprodrug thereof and a DGAT inhibitor, wherein the DGAT inhibitor has thefollowing formula

or a stereochemically isomeric form thereof, wherein A represents CH orN; the dotted line represents an optional bond in case A represents acarbon atom; X represents —C(═O)—; —O—C(═O)—; —C(═O)—C(═O)—;—NR^(x)—C(═O)—; —Z¹—C(═O)—; —Z¹—NR^(x)—C(═O)—; —C(═O)—Z¹—;—NR^(x)—C(═O)—Z¹—; —S(═O)p-; —C(═S)—; —NR^(x)—C(═S)—; —Z¹—C(═S)—;—Z¹—NR—C(═S)—; —C(═S)—Z¹—; or —NR^(x)—C(═S)—Z¹—; Z¹ represents abivalent radical selected from C₁₋₆alkanediyl, C₂₋₆alkenediyl orC₂₋₆allcynediyl; wherein each of said C₁₋₆alkanediyl, C₂₋₆alkenediyl orC₂₋₆allcynediyl may optionally be substituted with hydroxyl or amino;and wherein two hydrogen atoms attached to the same carbon atom inC₁₋₆alkanediyl may optionally be replaced by C₁₋₆alkanediyl; Yrepresents NR^(x)—C(═O)—Z²—; —NR^(x)—C(═O)—Z²NR^(y)—;—NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—; —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—O—;—NR^(x)—C(═O)—Z²—O—; —NR^(x)—C(═O)—Z²—O—C(═O)—; —NR^(x)—C(═O)—Z²—C(═O)—;—NR^(x)—C(═O)—Z²—C(═O)—O—; —NR^(x) —C(═O)—O—Z²—C(═O)—;—NR^(x)—C(═O)—O—Z²—C(═O)—O—; —NR^(x)—C(═O)—O—Z²—O—C(═O)—;—NR^(x)—C(═O)—Z²—C(═O)—NR^(y)—; —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—NR^(y)—;—C(═O)—Z²—; —C(═O)—Z²—O—; —C(═O)—NR^(x)—Z²—; —C(═O)—NR^(x)—Z²—O—;—C(═O)—NR^(x)—Z²—C(═O)—O—; —C(═O)—NR^(x)—Z²—O—C(═O)—;—C(═O)—NR^(x)—O—Z²—; —C(═O)—NR^(x)—Z²—NR^(y)—;—C(═O)—NR^(x)—Z²—NR^(y)—C(═O)—; or —C(═O)—NR^(x)—Z²—NR^(y)—C(═O)—O—; Z²represents a bivalent radical selected from C₁₋₆alkanediyl,C₂₋₆alkenediyl or C₂₋₆alkynediyl; wherein each of said C₁₋₆alkanediyl,C₂₋₆alkenediyl or C₂₋₆alkynediyl may optionally be substituted withC₁₋₄alkyloxy, C₁₋₄alkylthio, hydroxyl, cyano or aryl; and wherein twohydrogen atoms attached to the same carbon atom in the definition of Z²may optionally be replaced by C₁₋₆alkanediyl; R^(x) represents hydrogenor C₁₋₄alkyl; R^(y) represents hydrogen; C₁₋₄alkyl optionallysubstituted with C₃₋₆cycloalkyl or aryl or Het; C₂₋₄alkenyl; or—S(═O)_(p)-aryl; R¹ represents C₁₋₁₂alkyl optionally substituted withcyano, C₁₋₄alkyloxy, C₁₋₄alkyl-oxyC₁₋₄alkyloxy, C₃₋₆cycloalkyl or aryl;C₂₋₆alkenyl; C₂₋₆alkynyl; C₃₋₆cycloalkyl; adamantanyl; aryl¹;aryl¹C₁₋₆alkyl; Het¹; or Het¹C₁₋₆alkyl; provided that when Y represents—NR^(x)—C(═O)—Z²—; —NR^(x)—C(═O)—Z²—NR^(y);—NR^(x)—C(═O)—Z²—C(═O)—NR^(y)—; —C(═O)—Z²—;—NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—NR^(y)—; —C(═O)—NR^(x)—Z²—;—C(═O)—NR^(x)—O—Z²—; or —C(═O)—NR^(x)—Z²—NR^(y)—; then R¹ may alsorepresent hydrogen; R² represents hydrogen, C₁₋₁₂alkyl, C₂₋₆alkenyl orR³; R³ represents C₃₋₆cycloalkyl, phenyl, naphthalenyl,2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl,2,3-dihydrobenzofuranyl or a 6-membered aromatic heterocycle containing1 or 2 N atoms, wherein said C₃₋₆cycloalkyl, phenyl, naphthalenyl,2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl or 6-membered aromaticheterocycle containing 1 or 2 N atoms may optionally be substituted withat least one substituent, each substituent independently selected fromthe group consisting of hydroxyl; carboxyl; halo; C₁₋₆alkyl optionallysubstituted with hydroxy; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionallysubstituted with C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhalo-C₁₋₆alkyloxy;C₁₋₆alkyloxycarbonyl wherein C₁₋₆alkyl may optionally be substitutedwith aryl; cyano; C₁₋₆alkylcarbonyl; nitro; amino; mono-ordi(C₁₋₄alkyl)amino; C₁₋₄alkylcarbonylamino; —S(═O)_(p)—C₁₋₄alkyl;R⁵R⁴N—C(═O)—; R⁵R⁴N—C₁₋₆alkyl; C₃₋₆cycloalkyl; C₃₋₆cycloalkylC₁₋₄alkyl;C₃₋₆cycloalkyl-C(═O)—; aryl; aryloxy; arylC₁₋₄alkyl;aryl-C(═O)—C₁₋₄alkyl; aryl-C(═O)—; Het; HetC₁₋₄alkyl;Het-C(═O)—C₁₋₄alkyl; Het-C(═O)—; and Het-O—; R⁴ represents hydrogen;C₁₋₄alkyl optionally substituted with hydroxyl or C₁₋₄alkyloxy;R⁷R⁶N—C₁₋₄alkyl; C₁₋₄alkyloxy; Het; Het-C₁₋₄alkyl; aryl; orR⁷R⁶N—C(═O)—C₁₋₄alkyl; R⁵ represents hydrogen or C₁₋₄alkyl; R⁶represents hydrogen; C₁₋₄alkyl; or C₁₋₄alkylcarbonyl; R⁷ representshydrogen or C₁₋₄alkyl; or R⁶ and R⁷ may be taken together with thenitrogen to which they are attached to form a saturated monocyclic 5, 6or 7-membered heterocycle which may further contain one or moreheteroatoms each independently selected from the group consisting of O,S, S(═O)_(p) and N; and which heterocycle may optionally be substitutedwith C₁₋₄alkyl; R⁸ represents hydrogen; halo; C₁₋₄alkyl; or C₁₋₄alkylsubstituted with hydroxyl; aryl represents phenyl or phenyl substitutedwith at least one substituent, each substituent independently beingselected from the group consisting of hydroxyl; carboxyl; halo;C₁₋₆alkyl optionally substituted with C₁₋₄alkyloxy, amino or mono-ordi(C₁₋₄alkyl)amino; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionallysubstituted with C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy;C₁₋₆alkyloxycarbonyl; cyano; aminocarbonyl; mono-ordi(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono-ordi(C₁₋₄alkyl)amino; and —S(═O)_(p)—C₁₋₄alkyl; aryl¹ represents phenyl,naphthalenyl or fluorenyl; each of said phenyl, naphthalenyl orfluorenyl optionally substituted with at least one substituent, eachsubstituent independently being selected from the group consisting ofhydroxyl; oxo; carboxyl; halo; C₁₋₆alkyl optionally substituted withcarboxyl, C₁₋₄alkyloxycarbonyl or aryl-C(═O)—; hydroxyC₁₋₆alkyloptionally substituted with aryl or aryl-C(═O)—; polyhaloC₁₋₆alkyl;C₁₋₆alkyloxy optionally substituted with C₁₋₄alkyloxy; C₁-6alkylthio;polyhaloC₁₋₆alkyloxy; C₁₋₆alkyloxy-carbonyl wherein C₁₋₆alkyl mayoptionally be substituted with aryl; cyano; aminocarbonyl; mono-ordi(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono-ordi(C₁₋₆alkyl)amino; R⁵R⁴N—C₁₋₆alkyl; C₃₋₆cycloalkyl-NR^(x)—;aryl-NR^(x)—; Het-NR^(x)—; C₃₋₆cycloalkylC₁₋₄alkyl-NR^(x)—;arylC₁₋₄alkyl-NR^(x)—; HetC₁₋₄alkyl-NR^(x)—;—S(═O)_(p)—C₁₋₄alkyl;C₃₋₆cycloalkyl; C₃₋₆cycloalkylC₁₋₄alkyl; C₃₋₆cycloalkyl-C(═O)—; aryl;aryloxy; arylC₁₋₄alkyl; aryl-C(═O)—C₁₋₄alkyl; aryl-C(═O)—; Het;HetC₁₋₄alkyl; Het-C(═O)—C₁₋₄alkyl; Het-C(═O)—; and Het-O—; Hetrepresents a monocyclic non-aromatic or aromatic heterocycle containingat least one heteroatom each independently selected from the groupconsisting of O, S, S(═O)_(p) and N; or a bicyclic or tricyclicnon-aromatic or aromatic heterocycle containing at least one heteroatomeach independently selected from the group consisting of O, S, S(═O)_(p)and N; said monocyclic heterocycle or said bi-or tricyclic heterocycleoptionally being substituted with at least one substituent, eachsubstituent independently being selected from the group consisting ofhydroxyl; oxo; carboxyl; halo; C₁₋₆alkyl optionally substituted withC₁₋₄alkyloxy, amino or mono-or di(C₁₋₄alkyl)amino; polyhaloC₁₋₆alkyl;C₁₋₆alkyloxy optionally substituted with C₁₋₄alkyloxy; C₁₋₆alkylthio;polyhaloC₁₋₆alkyloxy; C₁₋₆alkyloxycarbonyl; cyano; aminocarbonyl;mono-or di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino;mono-or di(C₁₋₄alkyl)amino; and —S(═O)_(p)—C₁₋₄alkyl; Het¹ represents amonocyclic non-aromatic or aromatic heterocycle containing at least oneheteroatom each independently selected from the group consisting of O,S, S(═O)_(p) and N; or a bicyclic or tricyclic non-aromatic or aromaticheterocycle containing at least one heteroatom each independentlyselected from the group consisting of O, S, S(═O)_(p) and N; saidmonocyclic heterocycle or said bi-or tricyclic heterocycle optionallybeing substituted with at least one substituent, each substituentindependently being selected from the group consisting of hydroxyl; oxo;carboxyl; halo; C₁₋₆alkyl optionally substituted with carboxyl,C₁₋₄alkyloxycarbonyl or aryl-C(═O)—; hydroxyC₁₋₆alkyl optionallysubstituted with aryl or aryl-C(═O)—; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxyoptionally substituted with C₁₋₄alkyloxy; C₁₋₆alkylthio;polyhaloC₁₋₆alkyloxy; C₁₋₆alkyloxy-carbonyl wherein C₁₋₆alkyl mayoptionally be substituted with aryl; cyano; aminocarbonyl; mono-ordi(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono-ordi(C₁₋₆alkyl)amino; R⁵R⁴N—C₁₋₆alkyl; C₃₋₆cycloalkyl-NR^(x)—;aryl-NR^(x)—; Het-NR^(x)—; C₃₋₆cycloalkylC₁₋₄alkyl-NR^(x)—;arylC₁₋₄alkyl-NR^(x)—; HetC₁₋₄alkyl-NR^(x)—; —S(═O)_(p)—C₁₋₄alkyl;C₃₋₆cycloalkyl; C₃₋₆cycloalkylC₁₋₄alkyl; C₃₋₆cycloalkyl-C(═O)—; aryl;aryloxy; arylC₁₋₄alkyl; aryl-C(═O)—C₁₋₄alkyl; aryl-C(═O)—; Het;HetC₁₋₄alkyl; Het-C(═O)—C₁₋₄alkyl; Het-C(═O)—; and Het-O—; p represents1 or 2; provided that if X represents —O—C(═O)—, then R² represents R³;a N-oxide thereof, a pharmaceutically acceptable salt thereof or asolvate thereof.
 2. The combination according to claim 1 wherein theDGAT inhibitor is:N-[4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]phenyl]-4-methoxy-benzeneacetamide;4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide;4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]hydroxyacetyl]-1-piperazinyl]-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide;4-[4-[[2,6-dichloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide;4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide;4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]hydroxyacetyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide;4-[4-[[2,6-dichloro-4-[(4-ethyl-1-piperazinyl)methyl]phenyl]acetyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide;4-[4-[[2,6-dichloro-4-[(4-ethyl-1-piperazinyl)methyl]phenyl]acetyl]-1-piperazinyl]-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide;4-[4-[[2,6-dichloro-4-[[4-(methylsulfonyl)-1-piperazinyl]methyl]phenyl]acetyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide;4-[4-[[4-[(4-acetyl-1-piperazinyl)methyl]-2,6-dichlorophenyl]acetyl]-1-piperazinyl]-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide;4-[4-[[2,6-dichloro-4-[[4-(methylsulfonyl)-1-piperazinyl]methyl]phenyl]acetyl]-1-piperazinyl]-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide;4-[4-[[4-[(4-acetyl-1-piperazinyl)methyl]-2,6-dichlorophenyl]acetyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide;N-[4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]hydroxyacetyl]-1-piperazinyl]phenyl]-4-methoxy-benzeneacetamide;N-[4-[4-[[2,6-dichloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]phenyl]-4-methoxy-benzeneacetamide;4-[4-[[2,6-dichloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide;or a stereochemically isomeric form thereof; or a N-oxide thereof, apharmaceutically acceptable salt thereof or a solvate thereof.
 3. Thecombination according to claim 1 wherein the PPAR-α agonist or a prodrugthereof is a fibrate.
 4. The combination according to claim 3 whereinthe fibrate is fenofibrate.
 5. A combination according to claim 1 forreducing food intake, for reducing weight, for suppressing appetite, orinducing satiety.
 6. A compound or a stereochemically isomeric formthereof, wherein the compound isN-[4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]phenyl]-4-methoxy-benzeneacetamide;4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide;4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]hydroxyacetyl]-1-piperazinyl]-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide;4-[4-[[2,6-dichloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide;4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide;4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]hydroxyacetyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide;4-[4-[[2,6-dichloro-4-[(4-ethyl-1-piperazinyl)methyl]phenyl]acetyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide;4-[4-[[2,6-dichloro-4-[(4-ethyl-1-piperazinyl)methyl]phenyl]acetyl]-1-piperazinyl]-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide;4-[4-[[2,6-dichloro-4-[[4-(methylsulfonyl)-1-piperazinyl]methyl]phenyl]acetyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide;4-[4-[[4-[(4-acetyl-1-piperazinyl)methyl]-2,6-dichlorophenyl]acetyl]-1-piperazinyl]-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide;4-[4-[[2,6-dichloro-4-[[4-(methylsulfonyl)-1-piperazinyl]methyl]phenyl]acetyl]-1-piperazinyl]-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide;or4-[4-[[4-[(4-acetyl-1-piperazinyl)methyl]-2,6-dichlorophenyl]acetyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide;or a N-oxide thereof, a pharmaceutically acceptable salt thereof or asolvate thereof.
 7. A pharmaceutical composition comprising apharmaceutically acceptable carrier and a therapeutically effectiveamount of a combination according to claim
 1. 8. A pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound according to claim
 6. 9.The combination according to claim 1 wherein the DGAT inhibitor is

or a stereochemically isomeric form thereof; or a N-oxide thereof, apharmaceutically acceptable salt thereof or a solvate thereof; andwherein the PPAR agonist or a prodrug thereof is fenofibrate.